EP0490820A2 - Biphenylyl compounds - Google Patents

Abstract

Biphenylyl compounds of the formula <IMAGE> in which the variables R1, R2, R3, p, q and X and the rings A and B have the meanings given in Claim 1, in free form or in the salt form, can be prepared in a manner known per se and can be used, for example, as pharmaceutical active substances.

Description

worin R₁ ein aliphatischer Kohlenwasserstoffrest, der gebebenenfalls in höherer als der ß-Stellung zu dem in der Formel gezeigten Stickstoffatom durch Halogen oder Hydroxy substituiert ist, ein cycloaliphatischer Kohlenwasserstoffrest oder ein araliphatischer Kohlenwasserstoffrest ist; R₂ 1 H-Tetrazol-5-yl, Carboxy, verestertes Carboxy, amidiertes Carboxy, Amino, substituiertes Amino, Acylamino, Formyl, acetalisiertes Formyl, Hydroxy, verethertes Hydroxy, S(O)_m-R, wobei m 0, 1 oder 2 ist und R Wasserstoff oder ein aliphatischer Kohlenwasserstoffrest ist, Alkanoyl, Aminosulfonyl, N-substituiertes Aminosulfonyl, P0₂H₂, P0₃H₂ oder S-substituiertes Sulfonylamino bedeutet; R₃ Carboxy, 1H-Tetrazol-5-yl, S0₃H, P0₂H₂, P0₃H₂ oder Halogenalkansulfonylamino ist; X geradkettiges Alkylen, das gegebenenfalls aliphatisch überbrückt und/oder gegebenenfalls durch einen aliphatischen Kohlenwasserstoffrest substituiert ist, darstellt, oder für das Strukturelement der Formel-X₁-Ph-X₂-steht, wobei X₁ und X₂ unabhängig voneinander für eine Bindung oderfür Alkylen stehen und Ph gegebenenfalls substituiertes Phenylen bedeutet; die Ringe A und B unabhänbig voneinander unsubstituiert oder durch Halogen, Hydroxy, verethertes Hydroxy, S(O)_m R, wobei m 0, 1 oder 2 ist und RWasserstoff oder ein aliphatischer Kohlenwasserstoffrest ist, oder einen gegebenenfalls durch O unterbrochenen und/oder gebebenenfalls durch Halogen oder Hydroxy substituierten aliphatischen Kohlenwasserstoffrest substituiert sind und entweder p und q beide für 1 stehen oder p 0 ist und q 0 oder 1 darstellt; in freier Form oder in Salzform; die Verwendung dieser Verbindungen, ein Verfahren zur Herstellung dieser Verbindungen und pharmazeutische Präparate, enthaltend, in freier Form oder in Form eines pharmazeutisch verwendbaren Salzes, eine solche Verbindung I.The invention relates to biphenylyl compounds of the formula

wherein R _{1 is} an aliphatic hydrocarbon residue which is optionally substituted by halogen or hydroxy in a position higher than the β position to the nitrogen atom shown in the formula, a cycloaliphatic hydrocarbon residue or an araliphatic hydrocarbon residue; R ₂ 1 H-tetrazol-5-yl, carboxy, esterified carboxy, amidated carboxy, amino, substituted amino, acylamino, formyl, acetalized formyl, hydroxy, etherified hydroxy, S (O) _m -R, where m is 0, 1 or 2 is and R is hydrogen or an aliphatic hydrocarbon residue, alkanoyl, aminosulfonyl, N-substituted aminosulfonyl, P0 ₂ H ₂ , P0 ₃ H ₂ or S-substituted sulfonylamino; R _{3 is} carboxy, 1H-tetrazol-5-yl, S0 ₃ H, P0 ₂ H ₂ , P0 ₃ H ₂ or haloalkanesulfonylamino; X represents straight-chain alkylene which is optionally bridged by aliphatic means and / or is optionally substituted by an aliphatic hydrocarbon radical, or represents the structural element of the formula X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another for a bond or for Are alkylene and Ph is optionally substituted phenylene; the rings A and B independently of one another or unsubstituted by halogen, hydroxy, etherified hydroxyl, S (O) _m R, where m is 0, 1 or 2 and R is hydrogen or an aliphatic hydrocarbon radical, or one which is optionally interrupted by O and / or optionally are substituted by halogen or hydroxy substituted aliphatic hydrocarbon and either p and q are both 1 or p is 0 and q is 0 or 1; in free form or in salt form; the use of these compounds, a process for the preparation of these compounds and pharmaceutical preparations containing, in free form or in the form of a pharmaceutically acceptable salt, such a compound I.

The compounds I can exist as salts, in particular pharmaceutically usable salts. If the compounds I have at least one basic center, they can form acid addition salts. These are, for example, with strong inorganic acids, such as mineral acids, such as sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as optionally substituted, for example, by halogen, C ₁ -C ₄ -alkanecarboxylic acids, such as acetic acid, such as optionally unsaturated dicarboxylic acids, for example Oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or like benzoic acid, or with organic sulfonic acids, such as optionally, for example by halogen, substituted C ₁ -C ₄ alkane or aryl sulfonic acids, for example methane or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed with an optionally additionally present basic center. Compounds I with at least one acidic group (for example COOH or 1 H-tetrazol-5-yl) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g. . B. ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl propyl amine, or a mono-, di- or trihydroxy-lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts can furthermore optionally be formed. Also included are salts which are not suitable for pharmaceutical uses and can be used, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts.

Rings A and B form a biphenylyl radical, with corresponding biphenyl-4-yl being preferred and the radical R ₃ preferably being located in a 2 position of ring B. Rinbe A and B are independently unsubstituted or substituted one or more times, for example two or three times, it being possible for the substituents to be selected from the group of the corresponding substituents listed above.

An aliphatic hydrocarbon radical is lower alkyl, lower alkenyl or, secondarily, lower alkynyl.

An aliphatic hydrocarbon radical substituted by halogen or hydroxy is halogeno-lower alkyl, lower alkenyl or lower alkynyl or hydroxy lower alkyl, lower alkenyl or lower alkynyl.

An aliphatic hydrocarbon residue which is substituted by halogen or hydroxy at a position higher than the β position to the nitrogen atom shown in the formula is an aliphatic hydrocarbon residue defined by halogen or hydroxy substituted above, but in which the carbon atoms (carbon atoms) in a - and β-position to the nitrogen atom shown in the formula are unsubstituted.

An aliphatic hydrocarbon radical which is interrupted by O is lower alkoxy-lower alkyl, lower alkenyl or lower alkynyl or lower alkenyloxy lower alkyl, lower alkenyl or lower alkynyl.

An aliphatic hydrocarbon residue substituted by halogen or hydroxy and interrupted by O is a previously defined O-interrupted aliphatic hydrocarbon residue which is substituted by halogen or hydroxy.

A cycloaliphatic hydrocarbon radical is cycloalkyl or secondarily cycloalkenyl.

An araliphatic hydrocarbon radical is phenyl-lower alkyl or, secondly, phenyl-lower alkenyl or lower-alkynyl.

Straight-chain alkylene which is bridged by aliphatic means straight-chain alkylene in which one or independently two methylene groups are replaced by cycloalk-1, 1-ylene.

Straight-chain alkylene which is substituted by an aliphatic hydrocarbon radical means straight-chain alkylene which is substituted, independently of one another, two, three or four times by lower alkyl, lower alkenyl or, secondarily, lower alkynyl.

Straight chain alkylene which is bridged and substituted by an aliphatic hydrocarbon radical is straight chain alkylene defined above which is substituted by an aliphatic hydrocarbon radical, in which one or independently two methylene groups of the methylene groups present in the corresponding unsubstituted straight chain alkylene group are represented by cycloalk-1,1 -ylene is (are) replaced.

Esterified carboxy is carboxy which is esterified by an alcohol whose alcoholic hydroxyl function is bonded to lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy-lower alkyl, lower alkenyl or lower alkynyl.

Amidated carboxy is carbamoyl, the amino group of which is unsubstituted or mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy lower alkylene.

Substituted amino is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or amino disubstituted by lower alkylene or lower alkyleneoxy lower alkylene.

Acylamino is amino monosubstituted by lower alkanoyl or benzoyl.

Acetalized formyl is diniederalkoxymethyl or 1,3-dioxacycloalk-2-yl.

Etherified hydroxy is lower alkoxy, lower alkenyloxy, phenoxy or benzyloxy.

Alkanoyl means lower alkanoyl.

N-substituted aminosulfonyl is aminosulfonyl in which the amino group is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy lower alkylene.

S-substituted sulfonylamino is sulfonylamino in which the sulfur atom of the sulfonylamino group is monosubstituted by lower alkyl, lower alkenyl, lower alkynyl, halogeno lower alkyl, lower alkenyl or lower alkynyl, phenyl lower alkyl, lower alkenyl or lower alkynyl or phenyl.

Above and below, phenyl in each case means unsubstituted or one or several times independently of one another, e.g. two or three times, e.g. phenyl substituted by (a) substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, lower alkyl and trifluoromethyl. This applies to phenyl radicals per se and to phenyl partial structures in all groups containing phenyl partial structures, i.e. H. in phenylene, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, benzoyl, phenoxy and benzyloxy groups.

Unless otherwise defined, the general terms used above and below have the meanings given below.

The term “lower” means that corresponding groups and compounds each contain 1 to and with 7, preferably 1 to and with 4, carbon atoms.

Halogen is especially halogen with an atomic number up to 35, i.e. H. Fluorine, chlorine or bromine, and further includes iodine.

Straight-chain alkylene is straight-chain lower alkylene, ie straight-chain C ₁ -C ₇ -alkylene, ie methylene, eth-1,2-ylene, prop-1,3-ylene, but-1,4-ylene, pent-1,5-ylene , Hex-1,6-ylene or hept-1,7-ylene, the numbering of the carbon atoms of these straight-chain alkylene groups being carried out in such a way that the carbon atom adjacent to group (0) p in formula 1 has the number 1 wears.

Haloalkanesulfonylamino means halogen-lower alkanesulfonylamino, ie halo-C ₁ -C ₇ -alkanesulfonylamino, and is, for example, trifluoromethane, difluoromethane, 1, 1,2-trifluoroethane or heptafluoropropane sulfonylamino. Halogen-C ₁ -C ₄ -alkanesulfonylamino is preferred.

Phenylene is 1,2-, 1,3- or 1,4-phenylene

Alkylene (X _i or X ₂ ) is in particular C ₁ -C ₇ alkylene, is straight-chain or branched and in particular means methylene, eth-1,2-ylene, prop-1,3-ylene, but-1,4- ylene, pent-1,5-ylene, prop-1,2-ylene, 2-methylprop-1,3- ylene or 2,2-dimethylprop-1,3-ylene. Straight-chain C ₁ -C ₃ alkylene is preferred.

Lower alkyl is C ₁ -C ₇ alkyl, ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical. C ₁ -C ₄ -alkyl is preferred.

Lower alkenyl means C ₃ -C ₇ alkenyl and is, for example, propen-2-yl, allyl or but-1-en-3-yl, -1-en-4-yl, -2-en-1-yl or -2 -en-2-yl. C ₃ -C ₅ alkenyl is preferred.

Lower alkynyl is C ₃ -C ₇ alkynyl and means z. B. Propargyl.

Halogen lower alkyl means in particular halogen-C ₁ -C ₄ -alkyl, such as trifluoromethyl, 2-chloro-1,1,2-trifluoroethyl, chloromethyl, 3,3,3-trifluoropropyl, 4-chlorobutyl or heptafluoropropyl.

Halogen lower alkenyl means in particular halogen-C ₃ -C ₅ -alkenyl, such as 3-chloroallyl.

Halogen lower alkynyl is especially halogen-C ₃ -C ₅ -alkynyl, such as 3-chloropropargyl.

Hydroxy-lower alkyl means in particular hydroxy-C ₁ -C ₄ -alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl.

Hydroxy-lower alkenyl means in particular hydroxy-C ₃ -C ₅ -alkenyl, such as 3-hydroxyallyl.

Hydroxy-lower alkynyl means in particular hydroxy-C ₃ -C ₅ -alkynyl, such as 3-hydroxypropargyl.

Lower alkoxy lower alkyl means C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 2- (n-propyloxy) ethyl or ethoxymethyl.

Lower alkoxy-lower alkenyl or lower alkynyl means C ₁ -C ₄ -alkoxy-C ₃ -C ₅ -alkenyl or -alkynyl.

Lower alkenyloxy lower alkyl means C ₃ -C ₅ alkenyloxy-C ₁ -C ₄ alkyl, such as 2-allyloxyethyl, and lower alkenyloxy lower alkenyl or lower alkynyl means C ₃ -C ₅ alkenyloxy-C ₃ -C ₅ alkenyl or - alkynyl.

Cycloalkyl is cyclo-lower alkyl, ie C ₃ -C ₇ cycloalkyl, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is cycloniederalkenyl, ie C ₃ -C ₇ -cydoalkenyl, and means e.g. B cyclopent-2-enyl or - 3-enyl or cyclohex-2-enyl or -3-enyl.

Phenyl-lower alkyl is phenyl-C ₁ -C ₄ alkyl and means e.g. B. benzyl or 1-or2-phenethyl, while phenyl-lower alkenyl or phenyl-lower alkynyl is phenyl-C ₃ -C ₅ -alkenyl or -alkynyl, e.g. B. 3-phenylallyl or 3-phenylpropargyl.

Cycloalk-1,1-ylene is cyclo-lower alk-1,1-ylene, ie C ₃ -C ₇ -cydoalk-1,1-ylene, ie cycloprop-1,1-ylene, cyclobut-1,1-ylene, Cyclopent-1,1-ylene, cyclohex-1,1-ylene or cyclohept-1,1-ylene.

Lower alkylene (which by definition does not have to be identical to the straight-chain alkylene X defined above) means C ₂ -C ₇ -alkylene, is straight-chain or branched and means in particular eth-1,2-ylene, prop-1,3-ylene, but -1,4-ylene, pent-1,5-ylene, prop-1,2-ylene, 2-methylprop-1,3-ylene or 2,2-dimethylprop-1,3-ylene. C ₂ -C ₅ alkylene is preferred.

Lower alkyleneoxy lower alkylene means C ₂ -C ₄ alkyleneoxy-C ₂ -C ₄ alkylene, e.g. B. ethyleneoxyethylene.

Lower alkanoyl means C ₁ -C ₇ alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C ₂ -C ₅ alkanoyl is preferred.

Halogen-lower alkanesulfonyl is halogen-C ₁ -C ₇ -alkanesulfonyl, such as trifluoromethanesulfonyl.

Diniederalkoxymethyl is especially di-C ₁ -C ₄ alkoxymethyl, e.g. B. dimethoxymethyl or diethoxymethyl.

1,3-dioxacycloalk-2-yl is 1,3-dioxa-C ₄ -C ₇ cycloalk-2-yl, e.g. B. 1,3-dioxacyclopent-2-yl or 1,3-dioxacyclohex-2-yl.

Lower alkoxy is C ₁ -C ₇ alkoxy, ie methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or corresponding pentyloxy, hexyloxy or heptyloxy. C ₁ -C ₄ alkoxy is preferred.

Lower alkenyloxy means C ₃ -C ₇ alkenyloxy and is, for example, allyloxy, but-2-en-1-yloxy or but-3-en-1-yloxy. C ₃ -C ₅ alkenyloxy is preferred.

Extensive pharmacological studies have shown that the compounds I and their pharmaceutically acceptable salts z. B. have pronounced angiotensin II antagonizing properties.

It is known that angiotensin-II has strong vasoconstrictive properties and also stimulates aldosterone secretion and thus causes a clear sodium / water retention. The consequence of angiotensin II activity manifests itself among other things in an increase in blood pressure.

The importance of angiotensin II antagonists is to suppress the vasoconstrictor and aldosterone secretion stimulating effects caused by angiotensin II by competitive inhibition of the binding of angiotensin II to the receptors.

The angiotensin II antagonizing properties of the compounds I and their pharmaceutically acceptable salts can be determined in the angiotensin II binding test. Smooth rat muscle cells from homogenized rat aorta are used. The solid centrifugate is suspended in 50 mM Tris buffer (pH 7.4) using peptidase inhibitors. The samples are incubated for 60 minutes at 25 ° C. with ¹²⁵ 1-angiotensin-II (0.175 nM) and a varying concentration of angiotensin-II or test substance. The incubation is then ended by adding sodium chloride buffered with ice-cold phosphate and it is filtered through Whatman GF / F filters. The filters are counted with a gamma counter. The IC ₅₀ values are determined from the dose-response curve. For the compounds 1 and their pharmaceutically usable salts, IC ₅₀ values from about 10 nM are determined.

To determine the angiotensin-II-induced vasoconstriction, studies on the isolated rabbit aortic ring can be used. For this purpose, aortic rings are prepared from each breast and fixed between 2 parallel clamps at an initial tension of 2 g. The rings are then immersed at 37 ° C in 20 ml of a tissue bath and gassed with a mixture of 95% O ₂ and 5% C0 ₂ . The isometric responses are measured. At 20 minute intervals, the rings are alternately stimulated with 10 nM angiotensin-II (hypertensin-CIBA) and 5 nM noradrenaline chloride. The rings are then incubated with selected concentrations of the test substances before treatment with the agonists. The data is analyzed with a Buxco digital computer. The concentrations that cause 50% inhibition of the initial control values are reported as IC ₅₀ values. IC ₅₀ values from about 5 nM are determined for the compounds I and their pharmaceutically usable salts.

That the compounds I and their pharmaceutically acceptable salts can reduce hypertension induced by angiotensin-II can be verified in the test model of the normotensive, anesthetized rat. After calibration of the preparations with 0.9% NaCl (1 ml / kg iv), noradrenaline (1 µg / kg iv) or angiotensin-II (0.3 µg / kg iv), increasing doses (3-6) of the test substance are injected intravenously by bolus injection , whereupon angiotensin-II or noradrenaline is applied at 5 minute intervals after each dose. Blood pressure is measured directly in the carotid artery and recorded with an on-line data acquisition system (Buxco). The specificity of angiotensin II antagonism is indicated by the selective inhibition of the pressure effect caused by angiotensin II, but not by the norepinephrine effect. In this test model, the compounds I and their pharmaceutically acceptable salts from a dose of about 0.3 mg / kg i.v. an inhibitory effect.

The antihypertensive activity of the compounds I and their pharmaceutically usable salts can also be manifested in the test model of the renal hypertensive rat. In male rats, hypertension is produced by narrowing a renal artery according to the Goldblatt method. Doses of the test substance are administered to the rats using a gastric tube. Control animals receive an equivalent volume of solvent. Blood pressure and heartbeat are measured indirectly in conscious animals using the tail clamp method of Gerold et al. [Helv. Physiol. Acta 24 (1966), 58] before the administration of the test substance or the solvent and during the course of the experiments at intervals. The pronounced antihypertensive effect can be achieved from a dose of approximately 30 mg / kg p.o. be detected.

Accordingly, the compounds I and their pharmaceutically acceptable salts e.g. can be used as active ingredients in antihypertensives, which e.g. used to treat high blood pressure and heart failure. An object of the invention is thus the use of the compounds I and their pharmaceutically acceptable salts for the preparation of corresponding medicaments and for the therapeutic treatment of high blood pressure and heart failure. The commercial preparation of the active substances is also included in the manufacture of the pharmaceuticals.

Preferred compounds of the formula are those in which R _{1 is} lower alkyl, lower alkenyl, lower alkynyl, halogen higher than the β position to the nitrogen atom shown in the formula, lower halogen lower alkyl, lower alkenyl or lower alkynyl, hydroxy higher than the β position to the is hydroxy lower alkyl, lower alkenyl or lower alkynyl, cyclo lower alkyl, cyclo lower alkenyl, phenyl lower alkyl or phenyl lower alkenyl or lower alkynyl shown in the formula; R ₂ 1 H-tetrazol-5-yl, carboxy, carboxy, which is esterified by an alcohol, the alcoholic hydroxy function of which is bonded to lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy-lower alkyl, lower alkenyl or lower alkynyl, carbamoyl, the amino group of which is unsubstituted or is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or is disubstituted by lower alkylene or lower alkyleneoxy lower alkylene, amino, by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl loalk-2-yl or independently di-substituted or di-substituted by lower alkylene or Niederalkylenoxyniederalkylen amino, mono-substituted by lower alkanoyl or benzoyl, amino, formyl, di-lower alkoxymethyl, 1,3-Dioxacyc-, hydroxy, lower alkoxy, lower alkenyloxy, phenoxy, benzyloxy, S (O) _m -R, where m is 0, 1 or and R Is hydrogen, lower alkyl, lower alkenyl or lower alkynyl, lower alkanoyl, aminosulfonyl, aminosulfonyl, in which the amino group is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy lower alkylene ₂ H ₂ , P0 ₃ H ₂ or sulfonylamino, in which the sulfur atom of the sulfonylamino group by lower alkyl, lower alkenyl, lower alkynyl, halogen-lower alkyl, lower alkenyl or lower alkynyl, phenyl lower alkyl, lower alkenyl or lower alkynyl or phenyl mono is R _{3 is} carboxy, 1 H-tetrazol-5-yl, S0 ₃ H, P0 ₂ H ₂ , P0 ₃ H ₂ or halogen-lower alkanesulfonylamino; X straight-chain lower alkylene, straight-chain lower alkylene in which one or, independently of one another, two methylene group (s) is (are) replaced by cycloniederalk-1,1-ylene, straight-chain lower alkylene which, one or independently of one another, is two, three or four times by lower alkyl , Lower alkenyl or lower alkynyl is substituted, or straight-chain lower alkylene which is mono- or independently substituted two, three or four times by lower alkyl, lower alkenyl or lower alkynyl and in which one or independently two methylene group (s) of the corresponding unsubstituted straight-chain lower alkylene group existing methylene groups is (are) replaced by cycloniederalk-1,1-ylene, or represents the structural element of the formula -X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another for a bond or for C ₁ - Are C ₇ alkylene and Ph is phenylene; where the rings A and B are independently unsubstituted or by halogen, hydroxy, lower alkoxy, lower alkenyloxy, phenoxy, benzyloxy, S (O) _m- R, where m is 0, 1 or 2 and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl, Lower alkyl, lower alkenyl, lower alkynyl, halogen-lower alkyl, lower alkenyl or lower alkynyl, hydroxy lower alkyl, lower alkenyl or lower alkynyl, lower alkoxy lower alkyl, lower alkenyl or lower alkynyl optionally substituted by halogen or hydroxy or lower alkenyloxy optionally substituted by halogen or hydroxy lower alkyl, lower alkenyl or lower alkynyl are substituted; and either p and q are both 1 or p is 0 and q is 0 or 1; where phenyl in phenyl radicals per se and in phenylene, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, benzoyl, phenoxy and benzyloxy groups in each case unsubstituted or singly or independently of one another by (one) substituents selected from the group consisting of Halogen, hydroxy, lower alkoxy, lower alkyl and trifluoromethyl, substituted phenyl; in free form or in salt form.

Compounds of the formula in which R ₁ is lower alkyl, lower alkenyl or cyclo-lower alkyl are particularly preferred; R ₂ 1 H-tetrazol-5-yl, carboxy, carboxy, which is esterified by an alcohol, the alcoholic hydroxy function of which is bonded to lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy-lower alkyl, lower alkenyl or lower alkynyl, carbamoyl, the amino group of which is unsubstituted or is mono or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or is disubstituted by lower alkylene or lower alkyleneoxy lower alkylene, amino, by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or independently di-substituted or di-substituted by lower alkylene or Niederalkylenoxyniederalkylen amino, mono-substituted by lower alkanoyl or benzoyl, amino, formyl, di-lower alkoxymethyl, 1,3-Dioxacycloalk-2-yl, hydroxy, lower alkoxy, lower alkenyloxy, phenoxy, benzyloxy, S (O) _m- R , where m is 0, 1 or 2 and R is what is lower, lower alkyl, lower alkenyl or lower alkynyl, lower alkanoyl, aminosulfonyl, aminosulfonyl, in which the amino group is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or by lower alkylene or lower alkyleneoxy lower alkylene, disubstituted ₂ H ₂ , P0 ₃ H ₂ or sulfonylamino, in which the sulfur atom of the sulfonylamino group is monosubstituted by lower alkyl, lower alkenyl, lower alkynyl, halogeno lower alkyl, lower alkenyl or lower alkynyl, phenyl lower alkyl, lower alkenyl or lower alkynyl or phenyl; R _{3 is} carboxy, 1 H-tetrazol-5-yl or halo-lower alkanesulfonylamino; X straight-chain lower alkylene, straight-chain lower alkylene in which a methylene group has been replaced by cycloniederalk-1,1-ylene, straight-chain lower alkylene which is mono- or independently substituted two, three or four times by lower alkyl, lower alkenyl or lower alkynyl, or straight-chain lower alkylene which is mono- or independently substituted twice by lower alkyl, lower alkenyl or lower alkynyl and in which a methylene group of the methylene groups present in the corresponding unsubstituted straight-chain lower alkylene group is replaced by cyclone lower alk-1, 1-ylene; or X stands for the structural element of the formula -X, -Ph-X ₂ -, where X ₁ and X ₂ independently of one another stand for a bond or for C ₁ -C ₇ -kytes and Ph denotes phenylene; rings A and B independently of one another or unsubstituted or by halogen, hydroxy, lower alkoxy, S (O) _m- R, where m is 0, 1 or 2 and R is hydrogen or lower alkyl, lower alkyl, halogeno-lower alkyl, hydroxy-lower alkyl, if appropriate lower alkoxy-lower alkyl substituted by halogen or hydroxy or lower alkenyloxy-lower alkyl optionally substituted by halogen or hydroxy; and either p and q are both 1 or p is 0 and q is 0 or 1; where phenyl in phenyl radicals per se and in phenylene, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, benzoyl, phenoxy and benzyloxy groups in each case unsubstituted or singly or independently of one another by (one) substituents selected from the group consisting of Halogen, hydroxy, lower alkoxy, lower alkyl and trifluoromethyl, substituted phenyl; in free form or in salt form.

Compounds of the formula 1 in which R _{1 is} lower alkyl or lower alkenyl are very particularly preferred; R ₁ 1 H-tetrazol-5-yl, carboxy, carboxy, which is esterified by an alcohol, the alcoholic hydroxy function of which is bonded to lower alkyl or lower alkoxy-lower alkyl, carbamoyl, the amino group of which is unsub is substituted or mono- or independently disubstituted by lower alkyl or phenyl-lower alkyl or is disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, amino, monosubstituted or disubstituted by lower alkyl or phenyl-lower alkyl, or amino disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, by lower alkanoyl amino monosubstituted , Lower alkoxy, phenoxy, benzyloxy, S (O) _m -R, where m is 0, 1 or 2 and R is hydrogen or lower alkyl, lower alkanoyl, aminosulfonyl, P0 ₂ H ₂ , P0 ₃ H ₂ or sulfonylamino, in which the sulfur atom the sulfonylamino group is monosubstituted by lower alkyl, halogen lower alkyl, phenyl lower alkyl or phenyl; R _{3 is} carboxy or 1H-tetrazol-5-yl; X represents straight-chain lower alkylene, straight-chain lower alkylene in which a methylene group has been replaced by cyclone-lower alk-1,1-ylene, or straight-chain lower alkylene which is mono- or independently substituted twice by lower alkyl, or X for the structural element of the formula -X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another represent a bond or C ₁ -C ₇ alkylene and Ph is phenylene; the rings A and B are independently unsubstituted or substituted by halogen, hydroxy, lower alkoxy, S (O) _m -R, where m is 0, 1 or 2 and R is hydrogen or lower alkyl, or lower alkyl; p is 0, q represents 0 or 1; and ring B is bound in the 4-position of ring A; wherein phenyl in phenylene, phenyl-lower alkyl, phenoxy and benzyloxy groups each represents unsubstituted or simply substituted by a substituent selected from the group consisting of halogen, lower alkoxy, lower alkyl and trifluoromethyl; in free form or in salt form.

Compounds of the formula in which the rings A and B are unsubstituted are particularly preferred; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form.

Particularly preferred are compounds of the formula wherein R _{1 is} C ₁ -C ₄ alkyl, such as propyl or butyl, or C ₃ -C ₅ alkenyl, such as allyl; R ₂ 1 H-tetrazol-5-yl, carboxy, C ₁ -C ₄ alkoxycarbonyl, such as methoxy or ethoxycarbonyl, carbamoyl, NC ₁ -C ₄ alkylcarbamoyl, such as N-methylcarbamoyl, N, N-di-C ₁ -C ₄ alkylcarbamoyl, such as N, N-dimethylcarbamoyl, C ₁ -C ₄ alkanoyl, such as acetyl, aminosulfonyl or sulfonylamino, in which the sulfur atom of the sulfonylamino group is monosubstituted by C ₁ -C ₄ alkyl, such as methyl ; R _{3 is} carboxy or 1H-tetrazol-5-yl; X straight-chain C ₁ -C ₇ alkylene, such as eth-1,2-ylene, prop-1,3-ylene, but-1,4-ylene or pent-1,5-ylene, in which a methylene group is represented by C ₃ -C ₇ cycloalk-1,1-ylene, such as cyclopent-1,1-ylene or cyclohex-1,1-ylene, is replaced, or straight-chain C ₁ -C ₇ alkylene, such as methylene, eth-1,2 -ylene, prop-1,3-ylene or but-1,4-ylene, which is mono- or independently substituted twice by C ₁ -C ₄ alkyl, such as methyl or ethyl; rings A and B are unsubstituted; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form.

Particularly preferred are compounds of the formula wherein R _{1 is} C ₁ -C ₄ alkyl, such as propyl or butyl, or C ₃ -C ₅ alkenyl, such as allyl; R ₂ 1 H-tetrazol-5-yl, carboxy, C ₁ -C ₄ alkoxycarbonyl, such as methoxy or ethoxycarbonyl, carbamoyl, NC ₁ -C ₄ alkylcarbamoyl, such as N-methylcarbamoyl, N, N-di-C ₁ -C ₄ alkylcarbamoyl, such as N, N-dimethylcarbamoyl, C ₁ -C ₄ alkanoyl, such as acetyl, aminosulfonyl or sulfonylamino, in which the sulfur atom of the sulfonylamino group is monosubstituted by C ₁ -C ₄ alkyl, such as methyl ; R _{3 is} carboxy or 1 H-tetrazol-5-yl; X stands for the structural element of the formula -X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another represent a bond or straight-chain C ₁ -C ₃ alkylene, in particular methylene, and Ph phenylene, such as 1,2- or 1,3-phenylene; rings A and B are unsubstituted; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form.

Compounds of the formula in which R _{1 is} C ₁ -C ₄ -alkyl, such as propyl or butyl, are particularly preferred; R _{2 is} carboxy, C ₁ -C ₄ alkoxycarbonyl, such as methoxycarbonyl, or carbamoyl; R _{3 is} 1H-tetrazol-5-yl; X straight-chain C ₁ -C ₇ alkylene, such as eth-1,2-ylene, prop-1,3-ylene, but-1,4-ylene or pent-1,5-ylene, in which a methylene group is represented by C ₃ -C ₇ cycloalk-1,1-ylene, such as cyclopent-1,1-ylene, is replaced, or straight-chain C ₁ -C ₇ alkylene, such as methylene, eth-1,2-ylene, prop-1,3 -ylene or but-1,4-ylene, which is mono- or independently substituted twice by C ₁ -C ₄ alkyl, such as methyl or ethyl; rings A and B are unsubstituted; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form.

Compounds of the formula in which R _{1 is} C ₁ -C ₄ -alkyl, such as propyl or butyl, are primarily preferred; R _{2 represents} carboxy; R _{3 is} H-tetrazol-5-yl; X straight-chain C ₁ -C ₇ alkylene, such as eth-1,2-ylene, prop-1,3-ylene, but-1,4-ylene or pent-1,5-ylene, in which a methylene group is represented by C ₃ -C ₇ -cycloalk-1,1-ylene, such as cyclopent-1,1-ylene, is replaced, or straight-chain C ₁ -C ₇ alkylene, such as methylene, eth-1,2-ylene, prop-1, 3-ylene or but-1,4-ylene, which is mono- or independently substituted twice by C ₁ -C ₄ alkyl, such as methyl or ethyl; rings A and B are unsubstituted; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form.

Compounds of the formula in which R _{1 is} C ₃ -C ₄ -alkyl, such as n-propyl or n-butyl, are primarily preferred is; R _{2 represents} carboxy; R _{3 is} H-tetrazol-5-yl; X is 2-methyl-but-1,3-ylene or is 1,3-propylene in which the ω-methylene group is replaced by cyclohex-1,1-ylene; rings A and B are unsubstituted; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form.

The compounds of the formula mentioned in the examples are particularly preferred in free form or in salt form.

• a) in einer Verbindung der Formel
  
  
  worin Z₁ einen in R₃ überführbaren Rest darstellt, oder in einem Salz davon Z₁ in R₃ überführt oder
• b) eine Verbindung der Formel
  

oder ein Salz davon mit einer Verbindunq der Formel

worin entweder C(=0)-Z₂ eine Carboxygruppe oder ein reaktionsfähiges Derivat davon darstellt und R₂' ein Rest R₂ ist oder worin R₂' und C(=0)-Z₂ gemeinsam die Gruppe -C(=O)-O-C(=O)- bilden, oder einem Salz davon umsetzt und jeweils, wenn erwünscht, eine verfahrensgemäss oder auf andere Weise erhältliche verbindung I, in freier Form oder in Salzform, in eine andere verbindung I überführt, ein verfahrensgemäss erhältliches Gemisch von Isomeren auftrennt und das gewünschte Isomere isoliert und/oder eine verfahrensgemäss erhältliche freie verbindung I in ein Salz oder ein verfahrensgemäss erhältliches Salz einer verbindung I in die freie verbindung I oder in ein anderes Salz überführt.The invention further relates to a process for the preparation of the compounds I and their salts, for example characterized in that

• a) in a compound of the formula
  
  
  wherein Z ₁ represents a convertible into R ₃ radical, or converted into a salt thereof, Z ₁ R ₃ or
• b) a compound of the formula
  

or a salt thereof with a compound of the formula

in which either C (= 0) -Z _{2 represents} a carboxy group or a reactive derivative thereof and R ₂ 'is a radical R ₂ or in which R ₂ ' and C (= 0) -Z ₂ together form the group -C (= O) -OC (= O) - form, or a salt thereof and, if desired, a compound I, obtainable according to the process or otherwise, in free form or in salt form, converted into another compound I, a mixture of isomers obtainable according to the process separates and isolates the desired isomer and / or converts a process-available free compound I into a salt or a process-obtainable salt of a compound I into the free compound I or another salt.

Salts of starting materials which have at least one basic center are corresponding acid addition salts, while salts of starting materials which have at least one acidic group are salts with bases, in each case as listed in connection with corresponding salts of compounds I above.

The reactions described above and below in the variants are carried out in a manner known per se, for example in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, with cooling, at room temperature or with heating as required , for example in a temperature range from about -80 ° C to the boiling point of the reaction medium, preferably from about - 10 ° to about +200 _° C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and / or under works in anhydrous conditions. Details of corresponding procedures and reaction conditions can in particular also be found in the examples.

Option A):

Residues Z _{1 which} can be converted into the variable R ₃ are, for example, cyano, mercapto, halogen, the group - N ₁ ⁺ A ^- , in which A ^- denotes an anion derived from an acid, amino, functional derivatives of COOH, S0 ₃ H, P0 ₃ H ₂ and PO ₂ H ₂ and protected 1 H-tetrazol-5-yl.

Residues Z _{1 which} can be converted into 1 H-tetrazol-5-yl R ₃ are, for example, cyano and protected 1 H-tetrazol-5-yl.

For the preparation of compounds I in which R _{3 is} 1H-tetrazot-5-yl, starting material II, for example, in which Z _{1 is} cyano, is used and this, for. B. in an inert solvent, such as in an aromatic or araliphatic hydrocarbon, e.g. B. in toluene or a xylene, preferably with heating, with an azide, e.g. B. with HN ₃ or in particular a salt such as alkali metal salt thereof or with an organotin azide such as tri-lower alkyl or triaryl-tin azide. Preferred azides are, for example, sodium and potassium azide and tri-C ₁ -C ₄ -alkyl, for example trimethyl or tributyltin azide, and triphenyltin azide.

Protecting groups of protected 1H-tetrazol-5-yl are the protecting groups usually used in tetrazole chemistry, in particular triphenylmethyl, optionally, e.g. with nitro, substituted benzyl, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy or ethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, and 2-cyanoethyl, furthermore lower alkoxy lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protective groups are split off using known methods. For example, Triphenylmethyl usually by hydrolysis, especially in the presence of an acid, e.g. B. in the presence of hydrogen halide, advantageously in an inert solvent, such as in a haloalkane or an ether, for. B. in dichloromethane or dioxane, and with heating, or by hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl e.g. by hydrogenolysis in the presence of a hydrogenation catalyst, methoxy or ethoxy methyl e.g. by treatment with a tri-lower alkyl such as triethyl or tributyl tin bromide, methylthiomethyl e.g. B. by treatment with trifluoroacetic acid, 2-cyanoethyl e.g. by hydrolysis, e.g. with sodium hydroxide solution, 2-methoxyethoxymethyl e.g. by hydrolysis, e.g. with hydrochloric acid, and benzyloxymethyl and phenacyl e.g. split off by hydrogenolysis in the presence of a hydrogenation catalyst.

A radical Z _{1 that} can be converted into S0 ₃ HR ₃ is, for example, the mercapto group. Starting compounds II having such a group are oxidized, for example, by oxidation processes known per se to give compounds I in which R _{3 is} SO ₃ H. Examples of oxidizing agents are inorganic peracids, such as peracids from mineral acids, e.g. B. periodic acid or persulfuric acid, organic peracids, such as percarbonate or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenesulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid, in Consider. The oxidation is often carried out in the presence of suitable catalysts, with suitable acids, such as optionally substituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of VI, being used as catalysts. Subgroup, for example molybdenum or tungsten oxide, are to be mentioned. The oxidation is carried out under mild conditions, for example at temperatures from about -50 ° to about + 100 ° C.

A group which can be converted into P0 ₃ H ₂ R ₃ is, for example, a group -N ₂ ⁺ A ^- , where A- is an anion of an acid, such as mineral acid. Corresponding diazonium compounds are reacted, for example, in a manner known per se with a P (III) halide, such as PCI ₃ or PBr ₃ , and worked up hydrolytically, it being possible to obtain those compounds I in which R _{3 is} P0 ₃ H ₂ .

Compounds I, wherein R _{3 is} P0 ₂ H ₂ , are obtained, for. B. by converting Z ₁ in a compound II, in which Z _{1 is} a functional derivative of P0 ₂ H ₂ , into P0 ₂ H ₂ .

The radical Z ₁ which can be converted into halobenalkanesulfonylamino R ₃ is, for example, amino in color. For the preparation of compounds 1 in which R _{3 is} halobenalkanesulfonylamino, corresponding anilines are reacted, for example, with a usually reactively esterified haloalkanesulfonic acid, optionally in the presence of a base. Preferred as reactive esterified halobenakanesulfonic acids are the corresponding halides, such as chlorides, e.g. B. trifluoromethanesulfonyl chloride, and the corresponding anhydrides, e.g. B. trifluoromethanesulfonic anhydride.

A Z ₁ radical which can be converted into COOH R _{3 represents} , for example, functionally modified carboxy, such as cyano, esterified or amidated carboxy, hydroxymethyl or formyl.

Esterified carboxy is, for example, carboxy esterified with an optionally substituted aliphatic, cycloaliphatic or aromatic alcohol. An aliphatic alcohol is, for example, a lower alkanol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol or tert-butanol, while a 3- to 8-membered cycloalkanol, such as cyclopentanol, for example, is used as the cycloaliphatic alcohol , -hexanol or -heptanol, comes into question. An aromatic alcohol is, for example, a phenol or a heterocyclic alcohol, which can each be substituted, especially hydroxypyridine, e.g. 2-, 3- or 4-hydroxypyridine.

Amidated carboxy is, for example, carbamoyl, monosubstituted by hydroxyl, amino or optionally substituted phenyl, mono- or disubstituted by lower alkyl or by 4- to 7-membered alkylene or 3-aza, 3-lower alkylaza, 3-oxa- or 3-thiaalkylene disubstituted carbamoyl. Examples are carbamoyl, N-mono- or N, N-diniederalkylcarbamoyl, such as N-methyl-, N-ethyl-, N, N-dimethyl-, N, N-diethyl- and N, N-dipropyl-carbamoyl, pyrrolidino - And piperidinocarbonyl, morpholino, piperazino, 4-methylpiperazino and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonyl substituted by lower alkyl, lower alkoxy and / or halogen.

Preferred functionally modified carboxy is lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl, and cyano.

Compounds I, in which R _{3 is} carboxy, can, for example, starting from compounds II, in which Z _{1 is} cyano or esterified or amidated carboxy, by hydrolysis, in particular in the presence of a base, or, starting from compounds II, in which Z _{1 is} hydroxymethyl or formyl , are produced by oxidation. The oxidation takes place, for example, in an inert solvent, such as in a lower alkane carboxylic acid, for example acetic acid, a ketone, for example acetone, an ether, for example tetrahydrofuran, a heterocyclic aromatic compound, for example pyridine, or in water, or in a mixture thereof, if necessary with cooling or Heating, for example in a temperature range from about 0 ° to about +150 _° C. The oxidizing agents used are, for example, oxidizing transition metal compounds, in particular those with elements of the 1st, VI. or VII. subgroup, in question. Examples include: silver compounds such as silver nitrate, oxide and picolinate, chromium compounds such as chromium trioxide and potassium dichromate, and manganese compounds such as potassium, tetrabutylammonium and benzyltriethylammonium permanganate. Other oxidizing agents are, for example, suitable compounds with elements from main group IV, such as lead dioxide, or halogen-oxygen compounds, such as sodium iodate or potassium periodate.

oder ein Salz davon mit einer Verbindung R2'-(X)q-(0)p-C(=0)-Z₂ (IV) oder einem Salz davon umsetzt, z. B. in analoger Weise wie unter der Verfahrensvariante b) für die Umsetzung von Verbindungen III und IV erläutert.The starting material II is accessible in analogy to known methods, for example by using a compound of the formula

or a salt thereof with a compound R2 '- (X) q- (0) pC (= 0) -Z ₂ (IV) or a salt thereof, e.g. B. in an analogous manner as explained in process variant b) for the reaction of compounds III and IV.

Compounds II obtainable in this way, in which R _{2 is} carboxy, can, if desired, be converted into compounds II in a manner known per se before the reaction to give compounds, in which R ₂ esterified carboxy, e.g. B. lower alkoxycarbonyl.

The compounds IV are known or can be prepared in a manner known per se.

worin Z₃ für eine nucleofuge Abgangsgruppe, wie Halogen, z. B. Chlor oder Brom, Hydroxy, Niederalkoxy, z. B. Methoxy oder Ethoxy, Niederalkylthio, z. B. Methylthio, gegebenenfalls substituiertes Amino, z. B. Amino, N-Niederalkylamino oder N,N-Diniederalkylamino, oder Sulfonyloxy, z. B. gegebenenfalls halogeniertes Niederalkansulfonyloxy oder gegebenenfalls substituiertes Benzolsulfonyloxy, wie Methan-, Ethan-, Trifluormethan-, Benzol- oder p-Toluol-sulfonyloxy, steht, oder einem Salz davon umsetzt.The compounds Ila are available in analogy to known methods, for. B. by using a compound of formula R ₁ -NH ₂ (Ilb) or a salt thereof in a conventional manner with a compound of formula

wherein Z ₃ for a nucleofugic leaving group, such as halogen, z. B. chlorine or bromine, hydroxy, lower alkoxy, e.g. B. methoxy or ethoxy, lower alkylthio, e.g. B. methylthio, optionally substituted amino, e.g. B. amino, N-lower alkylamino or N, N-di-lower alkylamino, or sulfonyloxy, e.g. B. optionally halogenated lower alkanesulfonyloxy or optionally substituted benzenesulfonyloxy, such as methane, ethane, trifluoromethane, benzene or p-toluenesulfonyloxy, or a salt thereof.

The compounds Ilb and Ilc are known (cf. EP 253,310) or can be prepared in a manner known per se

Variant b):

Reactive derivatives of a carboxy group C (= 0) -Z ₂ are, for example, activated esters derived from carboxy, reactive anhydrides and reactive cyclic amides.

Activated esters derived from carboxy are, for example, unsaturated esters on the linking carbon atom of the esterifying radical, for example esters of the vinyl ester type, such as vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; method of the activated vinyl ester), carbamoyl vinyl esters (obtainable, for example, by treatment the corresponding acid with an isoxazolium reagent; 1,2-oxazoiium or Woodward method) or 1-lower alkoxyvinyl ester (obtainable, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), esters of the amidinotype, such as N, N'-disubstituted Amino esters (obtainable, for example, by treating the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example N, N'-dicyclohexylcarbodiimide; carbodiimide method) or N, N-disubstituted amidino esters (obtainable, for example, by treating the corresponding acid with an N, N-disubstituted cyanamide; Cyanamide method), or suitable aryl esters, in particular phenyl esters substituted by electron-withdrawing substituents (obtainable, for example, by treating the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3, 4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide; method of the activated aryl esters), furthermore cyanomethyl ester (obtainable, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester) Method), thioesters, in particular optionally substituted, for example by nitro, phenylthioesters (obtainable, for example, by treating the corresponding acid with optionally substituted, for example by nitro, thiophenols, inter alia with the aid of the anhydride or carbodiimide method; method of the activated thiolesters) and in particular Amino or amido esters (obtainable, for example, by treating the corresponding S acid with an N-hydroxyamino or N-hydroxyamido compound or an activated derivative thereof, for example with N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornane or norbor-nan-2,3- dicarboximide, 1-hydroxybenzotriazole, a benzotriazol-1-yloxy-phosphonium salt or benzotriazol-1-yluronium salt or 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example after the anhydride or carbodiimide -Method; Activated N-hydroxyester method).

Reactive anhydrides derived from carboxy may preferably be mixed anhydrides, e.g. Anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), such as azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treating it with nitrous acid; azide method) , such as anhydrides with carbonic acid half-esters, for example Carbonic acid lower alkyl half-esters (obtainable, for example, by treating the corresponding acid with chloroformic acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; method of mixed O-alkyl carbonic acid anhydrides) , such as anhydrides with dihalogenated, in particular dichlorinated, phosphoric acid (obtainable, for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), such as anhydrides with other phosphoric acid derivatives (for example those which can be obtained with phenyl-N-phenylphosphoramidochloridate) or as anhydrides with phosphoric acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenyl-lower alkane carboxylic acid halide, for example phenylacetic acid, pivalic acid or trifluoroacetic acid) urechloride; method of mixed carboxylic acid anhydrides) or like anhydrides with organic sulfonic acids (available e.g. by treating a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as lower alkane or aryl, e.g. Methane or p-toluenesulfonic acid chloride; Method of mixed sulfonic anhydrides), but can also be symmetrical anhydrides (obtainable e.g. by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropine; method of symmetrical anhyrides).

Reactive cyclic amides derived from carboxy are in particular amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g. with imidazole (obtainable e.g. by treating the corresponding acid with N, N'-carbonyldiimidazole; imidazole method), or pyrazoles, e.g. with 3,5-dimethylpyrazole (obtainable e.g. via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

The condensation to produce the amide bond is carried out in a manner known per se, for example as in standard works [e.g. B. in "Houben-Weyl - Methods of Organic Chemistry" (Volume 15/11, 4th edition, Georg Thieme Verlag, Stuttgart, 1974), in "The Peptides" (ed .: E. Gross and J. Meienhofer, volumes 1 and 2, Academic Press, London and New York, 1979/1980) or in "Principles of Peptide Synthesis" (ed .: M. Bodanszky, Springer-Verlag, Berlin, 1984)].

The condensation can be carried out in the presence of one of the customary condensation agents. Common condensing agents are e.g. B. carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyl) - or especially dicyclohexyl-carbodiimide, furthermore suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, also activated phosphoric acid derivatives, e.g. Diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridat, bis (2-oxo-3-oxazolidinyl) phosphoric acid chloride or 1-benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate.

If desired, an organic base is added, for example a tri-lower alkylamine with bulky residues, for example ethyldiisopropylamine, or a heterocyclic base, for example pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine. The condensation of acid anhydrides with amines can be carried out, for example, in the presence of inorganic carbonates, for example alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate).

The condensation is preferably carried out in an inert, polar, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxamide, for example in formamide or N, N-dimethylformamide, in a halogenated hydrocarbon, for example in dichloromethane, carbon tetrachloride or chlorobenzene, in one Ketone, for example in acetone, in a cyclic ether, for example in tetrahydrofuran, in an ester, for example in ethyl acetate, or in a nitrile, for example in acetonitrile, or in mixtures thereof, if appropriate at a reduced or elevated temperature, for example in a temperature range of about -40 ° C to about +100 _° C, preferably from about -10 ° C to about +50 _° C, and optionally under an inert gas, for example in a nitrogen atmosphere.

Reactive derivatives of a carboxy group C (= 0) -Z ₂ can also be formed in situ.

In a particularly preferred embodiment for the preparation of compounds I in which R _{2 is} carboxy, anhydrides IV are advantageously used in which R ₂ 'and C (= 0) -Z ₂ together form the group -C (= O) -OC (= O) - form (method of internal anhydrides), e.g. B. corresponding, optionally substituted, Bemstein or glutaric anhydrides.

worin Z₃ für eine nucleofuge Abgangsgruppe, wie Halogen, z. B. Chlor oder Brom, Hydroxy, Niederalkoxy, z. B. Methoxy oder Ethoxy, Niederalkylthio, z. B. Methylthio, gegebenenfalls substituiertes Amino, z. B. Amino, N-Niederalkylamino oder N,N-Diniederalkylamino, oder Sultonyloxy, z. B. gegebenenfalls halogeniertes Niederalkansulfonyloxy oder gegebenenfalls substituiertes Benzolsulfonyloxy, wie Methan-, Ethan-, Trifluormethan-, Benzol- oder p-Toluol-sulfonyloxy, steht, oder einem Salz davon umsetzt.The compounds 111 are obtainable in analogy to known methods, e.g. B. by using a compound of formula IIb or a salt thereof in a conventional manner with a compound of formula

wherein Z ₃ for a nucleofugic leaving group, such as halogen, z. B. chlorine or bromine, hydroxy, lower alkoxy, e.g. B. methoxy or ethoxy, lower alkylthio, e.g. B. methylthio, optionally substituted amino, e.g. B. amino, N-lower alkylamino or N, N-di-lower alkylamino, or sultonyloxy, e.g. B. optionally halogenated lower alkanesulfonyloxy or optionally substituted benzenesulfonyloxy, such as methane, ethane, trifluoromethane, benzene or p-toluenesulfonyloxy, or a salt thereof.

The compounds Illa are known (cf. EP 253,310) or can be prepared in a manner known per se.

A compound I obtainable according to the process or in another way can be converted into another compound I in a manner known per se.

For example, a compound containing hydroxy can be etherified by methods known per se. The etherification can e.g. with an alcohol, such as a lower alkanol, or a reactive ester thereof. Suitable reactive esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower alkanesulfonates or optionally substituted benzenesulfonates, e.g. Chlorides, bromides, iodides or methane, benzene or p-toluene sulfonates. The etherification can e.g. in the presence of a base, e.g. B. an alkali metal hydride, hydroxide or carbonate or a basic amine. Conversely, corresponding ethers, such as lower alkoxy compounds, e.g. by means of strong acids such as mineral acids, e.g. Hydrobromic or iodic acid, which may advantageously be in the form of pyridinium halides, or by means of Lewis acids, e.g. Halides from elements of the 111th main group or the corresponding subgroups are cleaved. These reactions can be carried out with cooling or heating, e.g. in a temperature range from about -20 ° to about + 100 ° C, in the presence or absence of a solvent or diluent, under inert gas and / or under pressure and, if appropriate, in a closed vessel.

Lower alkylthio substituents can be oxidized in the usual way to corresponding lower alkane sulfinyl or sulfonyl. Examples of suitable oxidizing agents for the oxidation to the sulfoxide stage are anorbanic peracids, such as peracids from mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarbonic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenesulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is frequently carried out in the presence of suitable catalysts, with suitable acids, such as optionally substituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of VI, being used as catalysts. Subgroup, for example molybdenum or tungsten oxide, are to be mentioned. The oxidation is carried out under mild conditions, for example at temperatures from about -50 ° to about +100 _° C. The further oxidation to the sulfone stage can be carried out accordingly with dinitrogen tetroxide as a catalyst in the presence of oxygen at low temperatures, as can the direct oxidation of lower alkylthio to lower alkanesulfonyl. However, sets the oxidizing agent is usually added in excess.

If one of the variables has amino, corresponding compounds can be N- (ar) alkylated in a manner known per se; aminosulfonyl and carbamoyl N- (ar) alkyl can also be alkylated. The (ar) alkylation takes place, for example, with an (aryl) C ₁ -C ₇ alkyl halide, for example bromide or iodide, (aryl) C ₁ -C ₇ alkane sulfonate, for example with methanesulfonate or p-toluenesultonate , or a di-C ₁ -C ₇ alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride, but more basic condensing agents, such as alkali metal amides, hydrides or alcoholates, for example sodium amide, sodium hydride or sodium ethanolate, may be required.

In a manner known per se, amino can further be acylated to acylamino, e.g. B. in an analogous manner as described in process variant b).

In compounds I which have an esterified or amidated carboxy group as a substituent, such a group can be used in a conventional manner, e.g. by means of hydrolysis, e.g. convert to the free carboxy group in the presence of a basic agent or an acidic agent such as a mineral acid.

In a particularly preferred embodiment of the process, process variant a) can be combined with the saponification of a carboxylic ester group R ₂ , for example a compound II in which Z _{1 is} cyano and R _{2 is} esterified carboxy, in particular lower alkoxycarbonyl, can be converted into a compound I in one step in which R _{2 is} carboxy and R ₃ 1 is H-tetrazol-5-yl. Corresponding advantageous procedures and reaction conditions can be found in the examples.

Furthermore, in compounds I which have a carboxy group as substituents (in particular if R _{3 is} different from carboxy), this can be done, for example, by treatment with an alcohol, such as a lower alkanol, in the presence of a suitable esterifying agent, such as an acidic reagent, for example an inorganic or organic acid or a Lewis acid, e.g. B. of zinc chloride, or a water-binding condensing agent, for example a carbodiimide, such as N, N'-dicyclohexylcarbodiimide, or by treatment with a diazo reagent, such as with a diazo-lower alkane, for example diazomethane, in an esterified carboxy group. These can also be obtained if compounds I in which the carboxy group is in free form or in salt, such as ammonium or metal, for example alkali metal, such as sodium or potassium salt form, are present with a C ₁ -C ₇ -alkyl halide, For example, methyl or ethyl bromide or iodide, or an organic sulfonic acid ester, such as a corresponding C ₁ -C ₇ alkyl ester, for example methanesulfonic acid or p-toluenesulfonic acid methyl ester or ethyl ester, treated.

Compounds I which have an esterified carboxy group as substituents can be obtained by transesterification, for example by treatment with an alcohol, usually with a higher alcohol than that corresponding to the esterified carboxy group in the starting material, in the presence of a suitable transesterification agent, such as a basic agent, for example one Alkali metal C ₁ -C ₇ alkanoate, -C ₁ -C ₇ alkanolate or cyanide, such as sodium acetate, methoxide, ethanolate, tert-butoxide or cyanide, or a suitable acidic agent, if appropriate converting the resulting alcohol, for example by distillation, into other ester compounds I. It is also possible to start from corresponding, so-called activated esters I which have an activated esterified carboxy group as substituents (see below) and convert these into another ester by treatment with a C ₁ -C ₇ -alkanol.

In compounds I which contain the carboxy group as substituents, they can also first be converted into a reactive derivative, such as an anhydride (also a mixed anhydride), an acid halide, for example chloride (for example by treatment with a thionyl halide, for example -chloride), an anhydride with a formic acid ester, for example -C ₁ -C ₇ alkyl ester (for example by treating a salt, such as an ammonium or alkali metal salt, with a halogen, such as chloro-formic acid ester, such as C ₁ -C _7- alkyl ester), or an activated ester, such as cyanomethyl, nitrophenyl, for example 4-nitro-phenyl, or polyhalophenyl, for example pentachlorophenyl ester (for example by treatment with a corresponding hydroxy compound in the presence of a suitable condensing agent, such as from N. , N'-dicyclohexylcarbodiimide), and then reacting such a reactive derivative with an amine and thus obtaining amide compounds I which have an amidated carboxy group as substituents. This can be obtained directly or via interconnections; for example, an activated ester, such as a 4-nitrophenyl ester, of a compound having a carboxy group can first be reacted with a 1-unsubstituted imidazole and the resulting 1-imidazolylcarbonyl compound reacted with an amine. However, other, non-activated esters, such as C ₁ -C ₇ alkyl esters, of compounds can be reacted with amines.

If an aromatic ring has a hydrogen atom as a substituent, it can be replaced with a halogen atom in the usual way using a halogenating agent, for example with bromine, hypobromic acid, an acyl hypobromite or another organic bromine compound, for example N-bromosuccinimide, N-bromoacetamide, N -Bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or 2,4,4,6-tetrabromo-2,5-cyclohexandien-1-one, by bromine or with elemental chlorine, for example in a halogen hydrocarbon, such as chloroform, and with cooling, for example down to about -10 ° C., by chlorine.

Formyl can be used in a conventional manner, e.g. B. be converted into acetalized formyl by reaction with a lower alkanol or a lower alkanediol.

If the compounds I contain unsaturated radicals, such as lower alkenyl or lower alkynyl groups, they can be converted into saturated radicals in a manner known per se. For example, the hydrogenation of multiple bonds is carried out by catalytic hydrogenation in the presence of hydrogenation catalysts, for which, for example, nickel, such as Raney nickel, and noble metals or their derivatives, for example oxides, are suitable, such as palladium or platinum oxide, which, if appropriate, on support materials, for example on carbon or calcium carbonate. The hydrogenation can preferably be carried out at pressures between about 1 and about 100 at and at temperatures between about -80 ° and about +200 _° C, especially between room temperature and about 100 ° C. The reaction is conveniently carried out in a solvent such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkane carboxylic acid, for example acetic acid.

The invention particularly relates to the methods described in the examples.

Salts of compounds I can be prepared in a manner known per se. For example, acid addition salts of compounds I are obtained by treatment with a suitable acid or a suitable ion exchange reagent. Salts of compounds I can be converted into the free compounds I in a conventional manner, acid addition salts e.g. by treatment with an appropriate basic agent or ion exchange reagent.

Salts of compounds I can be converted into other salts of compounds I in a manner known per se.

Depending on the procedure or reaction conditions, the compounds I having salt-forming, in particular basic, properties can be obtained in free form or in the form of salts.

As a result of the close relationship between the compound I in free form and in the form of its salts, in the preceding and below, the free compound I or its salts may also be understood to mean the appropriate salts or the free compound I, if appropriate.

The compounds I including their salts of salt-forming compounds can also be obtained in the form of their hydrates and / or others, for. B. used for crystallization, include solvents.

Depending on the choice of starting materials and procedures, the compounds 1 and their salts can be in the form of one of the possible isomers or as a mixture thereof, e.g. depending on the number, absolute and relative configuration of the asymmetric carbon atoms as pure isomers, such as antipodes and / or diastereomers, or as mixtures of isomers, such as mixtures of enantiomers, e.g. B. racemates, diastereomer mixtures or racemate mixtures are present.

Diastereomer mixtures and racemate mixtures obtained can be separated into the pure diastereomers or racemates in a known manner on account of the physico-chemical differences in the constituents, for example by fractional crystallization. Enantiomer mixtures obtained, such as racemates, can be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds , e.g. using chiral crown ethers, whereby only one enantiomer is complexed, or by conversion into diastereomeric salts, e.g. by reacting a basic end product racemate with an optically active acid such as carboxylic acid e.g. Tartaric or malic acid, or sulfonic acid, e.g. Camphorsulfonic acid, and separation of the diastereomer mixture thus obtained, e.g. due to their different solubilities, in the diastereomers, from which the desired enantiomer can be released by the action of suitable agents. The more effective enantiomer is advantageously isolated.

The invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a derivative or salt and / or its racemates or antipodes or in particular forms under the reaction conditions.

In the process of the present invention, preference is given to using starting materials and intermediates which lead to the compounds I described at the outset as being particularly valuable. New starting materials and intermediates for the preparation of the compounds I, their use and a process for their preparation also form a subject of the invention, the variables R ₁ , R ₂ , R ₃ , p, q and X and the rings A and B the have the meanings given for the compounds 1.

The compounds 1 and their pharmaceutically usable salts can, preferably in the form of pharmaceutically usable preparations, be used in a method for the prophylactic and / or therapeutic treatment of the animal or human body, in particular as antihypertensive agents.

The invention therefore also relates to pharmaceutical preparations which contain a compound in free form or in the form of a pharmaceutically usable salt as active ingredient, and to a process for their preparation. These pharmaceutical preparations are those for enteral, such as oral, rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being contained alone or together with customary pharmaceutical auxiliaries. The pharmaceutical preparations contain e.g. from about 0.1% to 100%, preferably from about 1% to about 60%, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration are e.g. those in unit dosage forms, such as coated tablets, tablets, capsules or suppositories, and also ampoules. These are made in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after adding suitable auxiliaries, to tablets or dragee cores.

Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch paste, using e.g. of corn, wheat, rice or potato starch, gelatin, gum tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, such as the starches mentioned above, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate . Aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, possibly gastric juice-resistant coatings, whereby, among other things, Concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Colorants or pigments, e.g. for identification or for labeling different doses of active ingredient.

Other orally applicable pharmaceutical preparations are plug-in capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.

As rectally applicable pharmaceutical preparations, e.g. Suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material. The basic materials are e.g. liquid triglycerides, polyethylene glycols and paraffinic hydrocarbons in question.

For parenteral administration, primarily aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. Contain sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers.

The dosage of the active ingredient can depend on various factors, such as the mode of administration, warm-blooded species, age and / or individual condition. In normal cases, an approximate daily dose of approximately 10 mg to approximately 250 mg is to be estimated for a patient weighing approximately 75 kg when administered orally.

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.

Example 1:

A solution of 8.8 g (22.7 mmol) 3-methoxycarbonylpropanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 9.8 g (29.5 mmol) tributyltin azide in 100 ml of o-xylene is heated under reflux for 20 hours. The reaction mixture is then cooled to 20 ° and 100 ml of 1N potassium hydroxide solution are added. Stir for 2 hours vigorously, separates the aqueous phase and acidifies it with 2N hydrochloric acid. The resin which separates is extracted with ethyl acetate. The crude product obtained by evaporating the ethyl acetate phase is Mash chromatographed on 500 g of silica gel [toluene / isopropanol / glacial acetic acid (170: 30: 2)]. This gives 3-carboxypropanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide in the form of a light brown foam which has an R _r value of 0. 20 [toluene / isopropanol / glacial acetic acid (170: 30: 2)].

• a) Eine Lösung von 20,0 g (73,5 mmol) 4-Brommethyl-2'-cyano-biphenyl (EP 253,310, Seite 159) in 150 ml Dioxan wird mit 36 ml (367 mmol) Butylamin versetzt und das Gemisch 3 Stunden unter Rückfluss erhitzt. Dann wird das Reaktionsgemisch im Vakuum eingedampft und der Rückstand zwischen 300 ml Diethylether und 100 ml Wasser verteilt. Die etherische Phase wird zweimal mit Wasser gewaschen, getrocknet und eingedampft. Das so erhaltene Oel wird an 500 g Silicagel Mash-chromatographiert [Toluol/Methanol (19:1)]. Die das Produkt enthaltenden Fraktionen werden eingedampft und liefern so das N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amin in Form eines gelben Oels, das einen R_rWert von 0,34 [Toluol/Methanol (4:1)] aufweist.
• b) Eine Lösung von 6,0 g (22,7 mmol) N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amin und 13 ml Hünib-Base in 100 ml Ethylacetat wird tropfenweise unter Eiskühlung mit einer Lösung von 5,1 g (34 mmol) Bernsteinsäuremonomethylestermonochlorid in 20 ml Ethylacetat versetzt. Das Reaktionsgemisch wird 1 Stunde bei 0 bis 5° gerührt und dann mit 30 ml Wasser versetzt. Die organische Phase wird nacheinander mit 30 ml 2 N-Salzsäure, Wasser und gesättigter Kaliumhydrogencarbonatlösung gewaschen und betrocknet. Durch Abdampfen des Lösungsmittels erhält man das rohe 3-Methoxy-carbonylpropansäure-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid in Form eines Oels, das einen RrWertvon 0,32 [Toluol/Methanol (19:1)] besitzt.

The starting material can be produced, for example, as follows:

• a) A solution of 20.0 g (73.5 mmol) of 4-bromomethyl-2'-cyano-biphenyl (EP 253.310, page 159) in 150 ml of dioxane is mixed with 36 ml (367 mmol) of butylamine and the mixture 3 Heated under reflux for hours. The reaction mixture is then evaporated in vacuo and the residue is partitioned between 300 ml of diethyl ether and 100 ml of water. The ethereal phase is washed twice with water, dried and evaporated. The oil thus obtained is Mash chromatographed on 500 g of silica gel [toluene / methanol (19: 1)]. The fractions containing the product are evaporated to give the N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine in the form of a yellow oil which has an R _r value of 0.34 [toluene / methanol (4th : 1)] has.
• b) A solution of 6.0 g (22.7 mmol) of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine and 13 ml of Hünib base in 100 ml of ethyl acetate is added dropwise with ice cooling with a solution of 5.1 g (34 mmol) of succinic acid monomethyl ester monochloride in 20 ml of ethyl acetate. The reaction mixture is stirred at 0 to 5 ° for 1 hour and then mixed with 30 ml of water. The organic phase is washed successively with 30 ml of 2N hydrochloric acid, water and saturated potassium hydrogen carbonate solution and dried. Evaporation of the solvent gives the crude 3-methoxy-carbonylpropanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide in the form of an oil which has an Rr value of 0.32 [toluene / methanol (19: 1)].

Example 2:

A solution of 4.0 g (9.8 mmol) of 3-methoxycarbonyl-3-methyl-butanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 4.3 g (13 mmol) Tributyltin azide in 80 ml of o-xylene is reacted analogously to Example I for 24 hours. For the hydrolysis, the reaction mixture is stirred with 50 ml of 2N potassium hydroxide solution at 40 to 50 ° for 4 hours. The aqueous phase is separated off and acidified with 2N hydrochloric acid and the separated oil is extracted with ethyl acetate. After washing the ethyl acetate solution with water, drying over MgS0 ₄ and evaporation, the 3-carboxy-3-methyl-butanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4- ylmethyl] -amide in the form of a colorless foam which has an R _f value of 0.25 [toluene / isopropanol / glacial acetic acid (170: 30: 2)].

• a) Eine Lösung von 3,6 g (13,5 mmol) N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amin und 1,75 g (13,5 mmol) 2,2-Dimethylbemsteinsäureanhydrid in 50 ml Dioxan wird 5 Stunden unter Rückfluss erhitzt. Nach Eindampfen des Reaktionsgemisches erhält man das rohe 3-Carboxy-3-methyl-butansäure-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid, das bei 125 bis 131 schmilzt und roh weiterverwendet wird.
• b) Ein Gemisch aus 4,8 g (12,2 mmol) 3-Carboxy-3-methyl-butansäure-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid, 2,2 g (15,9 mmol) Kaliumcarbonat, 1,7 g (13,5 mmol) Dimethylsulfat und 50 ml N,N-Dimethylformamid wird 3 bis 4 Stunden bei 50 bis 60° Innentemperatur gerührt. Nach dem Abkühlen wird das ungelöste Material abfiltriert, das Filtrat im Vakuum eingedampft und der Rückstand in Ethylacetat gelöst. Nach Waschen, Trocknen und Eindampfen der Lösung im Vakuum erhält man ein Rohprodukt, das durch Flash-chromatographie gereinigt wird [Toluol/Methanol (75:1)]. Das so erhaltene 3-Methoxycarbonyl-3-methyl-butansäure-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid liegt in Form eines gelblichen Oels vor, das einen R_f-Wert von 0,20 [Toluol/Isopropanol/Eisessig (170:30:2)] aufweist.

The starting material can be produced, for example, as follows:

• a) A solution of 3.6 g (13.5 mmol) of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine and 1.75 g (13.5 mmol) of 2,2-dimethylsuccinic anhydride in 50 ml of dioxane is heated under reflux for 5 hours. After evaporation of the reaction mixture, the crude 3-carboxy-3-methyl-butanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide is obtained, which melts at 125 to 131 and is further used raw.
• b) A mixture of 4.8 g (12.2 mmol) of 3-carboxy-3-methyl-butanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide, 2.2 g (15 , 9 mmol) potassium carbonate, 1.7 g (13.5 mmol) dimethyl sulfate and 50 ml N, N-dimethylformamide is stirred for 3 to 4 hours at an internal temperature of 50 to 60 °. After cooling down the undissolved material is filtered off, the filtrate is evaporated in vacuo and the residue is dissolved in ethyl acetate. After washing, drying and evaporating the solution in vacuo, a crude product is obtained which is purified by flash chromatography [toluene / methanol (75: 1)]. The 3-methoxycarbonyl-3-methyl-butanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide thus obtained is in the form of a yellowish oil which has an R _f value of 0.20 [ Toluene / isopropanol / glacial acetic acid (170: 30: 2)].

Example 3:

A solution of 5.5 g (11.3 mmol) of 4-methoxycarbonyl-4-methyl-pentanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 4.9 g (14 , 2 mmol) of tributyltin azide in 50 ml of o-xylene is reacted and worked up analogously to Example 2. The 4-carboxy-4-methyl-pentanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide is thus obtained in the form of a beige-colored foam , which has an R _f value of 0.34 [toluene / isopropanol / glacial acetic acid (170: 30: 2)].

The starting material can be prepared, for example, as follows: To a solution of 3.0 g (11.3 mmol) of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine and 6.5 ml of Hünib base in A solution of 3.3 g (17 mmol) of 4-methoxycarbonyl-4-methyl-pentanoic acid chloride in 20 ml of ethyl acetate is added dropwise to 50 ml of ethyl acetate at 0 to 5 °. The reaction mixture is stirred for 1 hour and then worked up analogously to Example 1 b). This gives 4-methoxycarbonyl-4-methyl-pentanoic acid-N-butylN- (2'-cyanobiphenyl-4-ylmethyl) -amide in the form of an oil which has an R _f value of 0.27 [toluene / methanol ( 19: 1)] and is used raw.

Example 4:

A solution of 3.45 g of 3,3-dimethyl-4-methoxycarbonyl-butanoic acid-N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide and 11.3 g of tributyltin azide in 100 ml of xylene is used for 3 hours heated under reflux. Then 50 ml of 2N sodium hydroxide solution are added and the mixture is stirred at 60 ° for 90 minutes. After cooling, the aqueous phase is acidified and extracted once with 100 ml and twice with 40 ml of CH ₂ C1 ₂ . The dichloromethane phase provides a colorless foam after drying over Na ₂ S0 ₄ and removal of the solvents. Purification of the same by chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent gives the pure 4-carboxy-3,3-dimethyl-butanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.44 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

• a) 10,84 g 4-Brommethyl-2'-cyano-biphenyl werden bei Raumtemperatur mit 20 ml Propylamin vermischt. Das Gemisch wird 30 Minuten gerührt, wobei Erwärmung bis zur Rückflusstemperatur eintritt, dann mit 400 ml CH₂C1₂ verdünnt und mit 200 ml NaHC0₃-Lösung gewaschen. Die organische Phase wird über Na₂S0₄ getrocknet und im Vakuum von den Lösungsmitteln befreit, woraufhin ein gelbes Oel zurückbleibt. Reinigung desselben durch Chromatographie an Kieselgel 60 (40-63 µm) mit CH₂Cl₂/CH₃OH (98:2) als Laufmittel ergibt das reine N-(2'-Cyanobiphenyl-4-ylmethyl)-N-propyl-amin, das einen R_f-Wert von 0,15 [CH₂Cl₂/CH₃OH (95:5)] aufweist.
• b) Eine Lösung von 2,19 g N-(2'-Cyanobiphenyl-4-ylmethyl)-N-propyl-amin und 2,37 g 3,3-Dimethylglutarsäuremonomethylestermonochlorid in 100 ml CH₂C1₂ wird mit 1,83 ml Triethylamin versetzt und das Gemisch bei Raumtemperatur 2 Stunden gerührt. Zweimalige Extraktion mit je 50 ml Wasser und Ausziehen der wässriben Phase mit 40 ml CH₂C1₂ ergibt eine organische Phase, die nach üblichem Vorgehen nach Eindampfen das 3,3-Dimethyl-4-methoxycarbonyl-butansäure-N-(2'-cyanobiphenyl-4-ylmethyl)N-propyl-amid liefert, das einen R_f-Wert von 0,66 [CH₂Cl₂/CH₃OH (95:5)] aufweist.

The starting material can be produced, for example, as follows:

• a) 10.84 g of 4-bromomethyl-2'-cyano-biphenyl are mixed with 20 ml of propylamine at room temperature. The mixture is stirred for 30 minutes, warming up to the reflux temperature, then diluted with 400 ml of CH ₂ C1 ₂ and washed with 200 ml of NaHC0 ₃ solution. The organic phase is dried over Na ₂ S0 ₄ and freed from the solvents in vacuo, whereupon a yellow oil remains. Purification of the same by chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (98: 2) as the eluent gives the pure N- (2'-cyanobiphenyl-4-ylmethyl) -N-propylamine , which has an R _f value of 0.15 [CH ₂ Cl ₂ / CH ₃ OH (95: 5)].
• b) A solution of 2.19 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propylamine and 2.37 g of monomethyl 3,3-dimethylglutarate in 100 ml of CH ₂ C1 ₂ is mixed with 1.83 ml Triethylamine were added and the mixture was stirred at room temperature for 2 hours. Extraction twice with 50 ml of water each and extracting the aqueous phase with 40 ml of CH ₂ C1 ₂ gives an organic phase which, after evaporation in the usual way, gives 3,3-dimethyl-4-methoxycarbonyl-butanoic acid N- (2'-cyanobiphenyl) -4-ylmethyl) N-propyl-amide, which has an R _f value of 0.66 [CH ₂ Cl ₂ / CH ₃ OH (95: 5)].

Example 5:

A solution of 1.88 g of 4-methoxycarbonyl-4-methyl-pentanoic acid-N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide and 6.0 g of tributyltin azide in 50 ml of xylene is refluxed for 17 hours heated. The mixture is then evaporated, the residue is taken up in 25 ml of 2N sodium hydroxide solution and the aqueous mixture is extracted three times with 50 ml of diethyl ether each time. The aqueous phase is acidified and extracted once with 50 ml and twice with 25 ml of CH ₂ C1 ₂ . The crude product obtained from the CH ₂ C1 ₂ phase according to the usual procedure gives the pure 4-methoxycarbonyl-4- as the eluent after chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent. methyl-pentanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.59 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

The starting material can be prepared, for example, as follows: A solution of 2.50 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propylamine and 2.09 ml of triethylamine in 100 ml of CH ₂ C1 ₂ is mixed with 2 , 89 g of 4-methoxycarbonyl-4-methyl-pentanoic acid chloride were added and the mixture was stirred for 1 hour. The reaction mixture is washed twice with 50 ml of water each time and the combined aqueous phases are extracted with 50 ml of CH ₂ C1 ₂ . The crude product obtained from the organic phase according to the usual procedure is purified by chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (98: 2) as the eluent, and thus gives the pure 4-methoxycarbonyl-4- methyl-pentanoic acid-N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide, which has an R _r value of 0.56 [CH ₂ Cl ₂ / CH ₃ OH (95: 5)].

Example 6:

A solution of 0.450 g of 4-methoxycarbonyl-4-methyl-pentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide and 2.0 ml of 2 N- Potassium hydroxide solution in 10 ml of methanol is heated under reflux for 6 hours. The cooled mixture is acidified and evaporated. The residue is purified by chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent and thus gives the pure 4-carboxy-4-methyl-pentanoic acid-N-propyl- N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.40 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)] having.

Example 7:

A solution of 2.93 g of 4-carboxy-4-ethyl-hexanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 8.8 g of tributyltin azide in 75 ml of xylene is refluxed for 23 hours heated. The cooled mixture is extracted with 50 ml of 2N sodium hydroxide solution. The aqueous phase is acidified and extracted once with 100 ml and twice with 30 ml of CH ₂ C1 ₂ . After combined treatment, the combined dichloromethane phases provide a crude product which, after chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent, gives the pure 4-carboxy-4-ethylhexanoic acid N- butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _r value of 0.46 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)] has results.

The starting material can be prepared, for example, as follows: a solution of 3.2 g of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine and 3.09 g of 2,2-diethylglutaric anhydride in 50 ml of dioxane becomes 6 Heated to 115 ° (bath temperature) for hours. After evaporation of the reaction mixture, the residue is taken up in 100 ml of ethyl acetate and the ethyl acetate phase is washed twice with 50 ml of water each time, dried over Na ₂ SO ₄ and evaporated in vacuo. Chromatography of the evaporation residue on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent gives the pure 4-carboxy-4-ethyl-hexanoic acid-N-butyl-N- (2 ' -cyanobiphenyl-4-ylmethyl) -amide, which has an R _r value of 0.72 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

Example 8:

Analogously to Example 4, starting from 4.04 g of 2-ethoxycarbonylbutanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide, after chromatography of the crude product on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (9: 1) as eluent, the pure 2-carboxybutanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.56 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

The starting material can be prepared, for example, as follows: Analogously to Example 4b), starting from 2.64 g of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine and 2.68 g of ethylmalonic acid monoethyl ester monochloride, the 2-ethoxycarbonylbutanoic acid -N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide, which has an R _f value of 0.65 [CH ₂ Cl ₂ / CH ₃ OH (95: 5)].

Example 9:

Analogously to Example 4, starting from 4.20 g of 4-carboxy-4-ethyl-hexanoic acid N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide, after chromatography of the crude product on Kieselbel 60 (40- 63 µm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent, the pure 4-carboxy-4-ethyl-hexanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, which has an R _f value of 0.58 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

The starting material can be prepared, for example, as follows: A mixture of 2.50 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propylamine, 2.58 g of 2,2-diethylglutaric anhydride and 50 ml of dioxane becomes 1 Heated under reflux for one hour. After evaporation of the reaction mixture, the residue is taken up in 100 ml of ethyl acetate and the ethyl acetate phase is washed twice with 50 ml of water each time, dried over sodium sulfate and evaporated in vacuo. The 4-carboxy-4-ethyl-hexanoic acid N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide thus obtained is used crude.

Example 10:

Analogously to Example 4, starting from 4.19 g of 4-carboxy-3,3-tetramethylene-butanoic acid N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide, after chromatography of the crude product on silica gel 60 ( 40-63 µm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent, the pure 4-carboxy-3,3-tetramethylene-butanoic acid-N-propyl-N- [2 '- (1 H-tetrazole -5-yl) -biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.48 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

• Analog Beispiel 7a) werden 2,50 g N-(2'-Cyanobiphenyl-4-ylmethyl)-N-propyl-amin mit 2,02 g 3,3-Tetramethylenglutarsäureanhydrid umgesetzt. Nach extraktiver Aufarbeitung erhält man das 4-Carboxy-3,3-tetramethylen-butansäure-N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amid, das einen R_f-Wert von 0,80 [CH₂Cl₂/CH₃OH (4:1)] aufweist.

The starting material can be produced, for example, as follows:

• Analogously to Example 7a), 2.50 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propylamine are reacted with 2.02 g of 3,3-tetramethylene glutaric anhydride. After extractive work-up, 4-carboxy-3,3-tetramethylene-butanoic acid N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amide is obtained, which has an R _f value of 0.80 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

Example 11:

Analogously to Example 10, the 4-carboxy-3,3-tetramethylene-butanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.49 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

Example 12:

Analogously to Example 10, the 3-carboxy-3,3-tetramethylene-propanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which at 104 melts up to 109 °.

Example 13:

Analogously to Example 10, the 3-carboxy-3,3-tetramethylene-propanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which at 122 melts up to 127 °.

Example 14:

Analogously to Example 9, the 3-carboxy-3-ethyl-pentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which is at 105 to 114 ° melts, preserved.

Example 15:

• 1. das 4-Carboxy-4,4-tetramethylen-butansäure-N-propyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 2. das 4-Carboxy-4,4-tetramethylen-butansäure-N-butyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 3. das 2-Carboxy-2-ethyl-butansäure-N-butyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 4. das 2-Carboxy-2-ethyl-butansäure-N-propyl-N-[2'-(1H-tetrazol-5-yl)biphenyl4-ylmethyl]-amid;
• 5. das 2-Carboxybutansäure-N-propyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 6. das 3-Carboxy-3-ethyl-pentansäure-N-butyl-N-[2'-(1H-tetrazol-5-yl)biphenyl4-ylmethyl]-amid;
• 7. das 3-Carboxy-3,3-pentamethylen-propansäure-N-propyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 8. das 3-Carboxy-3,3-pentamethylen-propansäure-N-butyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 9. das 5-Carboxy-5,5-tetramethylen-pentansäure-N-propyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 10. das 5-Carboxy-5,5-tetramethylen-pentansäure-N-butyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 11. das 3-Carboxy-2,2-tetramethylen-propansäure-N-propyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 12. das 3-Carboxy-2,2-tetramethylen-propansäure-N-butyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amid;
• 13. das 2,2-Pentamethylen-2-trifluormethansulfonylamino-ethansäure-N-butyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amid; und
• 14. das 2,2-Pentamethylen-2-trifluormethansulfonylamino-ethansäure-N-propyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amid.

The following can also be obtained in a manner analogous to that described in one of the preceding examples:

• 1. the 4-carboxy-4,4-tetramethylene-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide;
• 2. the 4-carboxy-4,4-tetramethylene-butanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide;
• 3. the 2-carboxy-2-ethyl-butanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide;
• 4. the 2-carboxy-2-ethyl-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl4-ylmethyl] -amide;
• 5. the 2-carboxybutanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide;
• 6. the 3-carboxy-3-ethyl-pentanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl4-ylmethyl] amide;
• 7. the 3-carboxy-3,3-pentamethylene-propanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide;
• 8. the 3-carboxy-3,3-pentamethylene-propanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide;
• 9. 5-carboxy-5,5-tetramethylene-pentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide;
• 10. 5-carboxy-5,5-tetramethylene-pentanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide;
• 11. the 3-carboxy-2,2-tetramethylene-propanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide;
• 12. the 3-carboxy-2,2-tetramethylene-propanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide;
• 13. 2,2-pentamethylene-2-trifluoromethanesulfonylaminoethanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide; and
• 14. The 2,2-pentamethylene-2-trifluoromethanesulfonylaminoethanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide.

Example 16:

A solution of 2.58 g of 4-carboxy-4,4-pentamethylene-butanoic acid-N-propyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 8.0 g of tributyltin azide in 60 ml of xylene is Heated under reflux for 16 hours. The cooled down The mixture is stirred with 30 ml of 2N sodium hydroxide solution for 30 minutes. The aqueous phase is extracted three times with 50 ml of ether and then acidified and extracted three times with 50 ml of CH ₂ C1 ₂ . After combined treatment, the combined dichloromethane phases provide a crude product which, after chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as the eluent, 4-carboxy-4,4-pentamethylene-butanoic acid N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.48 [CH ₂ Cl ₂ / CH ₃ OH ( 4: 1)].

• Eine Lösung von 1,37 g N-(2'-Cyanobiphenyl-4-ylmethyl)-N-propyl-amin und 1,20 g 2-Oxaspiro[5.5]unde- can-1,3-dion in 30 ml Dioxan wird 3 Stunden unter Rückfluss erhitzt. Nach Entfernen des Lösungsmittels wird in 50 ml Essigester aufgenommen und zweimal mit 25 ml Wasser gewaschen. Die organische Phase liefert nach Trocknen und Eindampfen 4-Carboxy-4,4-pentamethylen-butansäure-N-propyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid.

The starting material can be produced, for example, as follows:

• A solution of 1.37 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amine and 1.20 g of 2-oxaspiro [5.5] undecan-1,3-dione in 30 ml of dioxane Heated under reflux for 3 hours. After removing the solvent, it is taken up in 50 ml of ethyl acetate and washed twice with 25 ml of water. After drying and evaporation, the organic phase gives 4-carboxy-4,4-pentamethylene-butanoic acid-N-propyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide.

Example 17:

Analogously to Example 16, starting from 2.63 g of 4-carboxy-4,4-pentamethylene-butanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 7.80 g of tributyltin azide, after chromatography on silica gel 60 (40-63 mm) with CH ₂ Cl ₂ / CH ₃ OH (95: 5) as eluent 4-carboxy-4,4-pentamethylene-butanoic acid-N-butyl-N- [2 '- (1 H -tetrazol5-yl) -biphenyl-4-ylmethyl] -amide, which has an R _f value of 0.32 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

• Analog Beispiel 16 werden 1,35 g N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amin mit 1,20 g 2-Oxa- spiro[5.5]undecan- 1,3-dion zu 4-Carboxy-4,4-pentamethylen-butansäure-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid umgesetzt.

The starting material can be produced, for example, as follows:

• Analogously to Example 16, 1.35 g of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine with 1.20 g of 2-oxaspiro [5.5] undecane-1,3-dione become 4-carboxy -4,4-pentamethylene-butanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide.

Example 18:

A solution of 2.76 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-isophthalic acid mono-amide and 8.68 g of tributyltin azide in 75 ml of xylene is heated under reflux for 2 hours. The cooled mixture is stirred with 50 ml of 2N sodium hydroxide solution at room temperature for 1 hour, then acidified and extracted with 100 ml and twice 50 ml of CH ₂ C1 ₂ . After combined treatment, the combined dichloromethane phases provide a crude product which, after chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (9: 1) as eluent, N-propyl-N- [2 '- (1 H-tetrazol-5-yl) -bipheny14-ylmethyl] -isophthalic acid mono-amide, which has an R _f value of 0.10 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

• Eine Lösung von 2,50 g N-(2'-Cyanobiphenyl-4-ylmethyl)-N-propyl-amin, 2,98 g Isophthalsäure-monomethylester-mono-chlorid und 2, 10 ml Triethylamin in 100 ml CH₂C1₂ wird 1 Stunde bei Raumtemperatur gerührt. Extraktion mit zweimal 50 ml Wasser und übliche Behandlung der organischen Phase liefert ein Rohprodukt, welches nach Chromatographie an Kieselgel 60 (40-63 µm) mit CH₂Cl₂ als Elutionsmittel N-(2'-Cyano- biphenyl-4-ylmethyl)-N-propyl-isophthalsäure-mono-amid, welches einen R_f-Wert von 0,61 [CH₂Cl₂/CH₃OH (4:1)] aufweist, ergibt.

The starting material can be produced, for example, as follows:

• A solution of 2.50 g of N- (2'-cyanobiphenyl-4-ylmethyl) -N-propyl-amine, 2.98 g of monomethyl isophthalate mono-chloride and 2.10 ml of triethylamine in 100 ml of CH ₂ C1 ₂ is stirred for 1 hour at room temperature. Extraction with twice 50 ml of water and conventional treatment of the organic phase gives a crude product which, after chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ as eluent, N- (2'-cyano-biphenyl-4-ylmethyl) - N-propyl-isophthalic acid mono-amide, which has an R _f value of 0.61 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)].

Example 19:

A solution of 2.50 g of 2-carboxy-phenylacetic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 6.50 g of tributyltin azide in 50 ml of xylene is heated under reflux for 15 hours. The cooled mixture is stirred with 50 ml of 2N sodium hydroxide solution for 30 minutes at room temperature. The aqueous phase is acidified and extracted three times with 50 ml CH ₂ Cl ₂ . After combined treatment, the combined dichloromethane phases give a crude product which, after chromatography on silica gel 60 (40-63 μm) with CH ₂ Cl ₂ / CH ₃ OH (97: 3)) as eluent, 2-carboxy-phenylacetic acid-N-butylN- [ 2 '- (1 H-tetrazol-5-yl) -bi phenyl-4-ylmethyl] -amide, which has an R _f value of 0.37 [CH ₂ Cl ₂ / CH ₃ OH (4: 1)] , results.

• a) Eine Lösung von 2,64 g N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amin und 2,43 g Homophthalsäureanhydrid in 50 ml Dioxan wird 1 Stunde unter Rückfluss erhitzt. Nach dem Entfernen des Lösungsmittels wird in 100 ml Essigester aufgenommen und mit zweimal 50 ml Wasser gewaschen. Die organische Phase liefert nach üblicher Behandlung ein Rohprodukt, welches aus CH₂C1₂/Ether/Hexan 2-Carboxy-phenylessigsäure-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amid, Smp. 137- 139⁰, ergibt.

The starting material can be produced, for example, as follows:

• a) A solution of 2.64 g of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine and 2.43 g of homophthalic anhydride in 50 ml of dioxane is heated under reflux for 1 hour. After removing the solvent, it is taken up in 100 ml of ethyl acetate and washed with twice 50 ml of water. After the usual treatment, the organic phase provides a crude product which consists of CH ₂ C1 ₂ / ether / hexane 2-carboxy-phenylacetic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide, mp. 137- 139 ⁰ , results.

Example 20: N-Butyl-3-methyl-N- (2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -2- (S) trifluoromethanesulfonylamino-butanoic acid amide

Analogously to Example 1, a crude product is obtained from 1.7 g (3.5 mmol) of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -3-methyl-2- (S) -trifluoromethanesulfonylamino-butanoic acid amide is flash chromatographed on 150 g of silica gel (eluent: ethyl acetate / ethanol / conc. ammonia (6: 3: 1)). The fractions containing the product (R _f value 0.22) are combined and evaporated in vacuo. The evaporation residue is distributed between ethyl acetate and 1N hydrochloric acid. The organic phase is separated off, washed with brine, dried and evaporated. The title compound is thus obtained as a beige foam (FAB-MS MH ⁺ = 539).

• Analog Beispiel 21c) erhält man unter Verwendung von 1,3 g (3,5 mmol) 2-(S)-Amino-N-butyl-N- (2'-cyano- biphenyl-4-ylmethyl)-3-methyl-butansäureamid, 1,0 ml (5,8 mmol) Hünig-Base und 1,3 g (4,6 mmol) Trifluormethansulfonsäure-anhydrid das N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-3-methyl-2-(S)-trifluormethansul- fonylaminobutansäureamid als rohes Oel, das ohne weitere Reinigung eingesetzt wird.

The starting material can be produced, for example, as follows:

• Analogously to Example 21c), 1.3 g (3.5 mmol) of 2- (S) -amino-N-butyl-N- (2'-cyano-biphenyl-4-ylmethyl) -3-methyl- butanoic acid amide, 1.0 ml (5.8 mmol) of Hünig base and 1.3 g (4.6 mmol) of trifluoromethanesulfonic acid anhydride the N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -3-methyl -2- (S) -trifluoromethanesulfonylaminobutanoic acid amide as a crude oil, which is used without further purification.

Example 21: 2- (S) -methanesulfonylamino-3-methyl-butanoic acid-N-butyl-N- (2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide

Analogously to Example 20, 2.2 g (5 mmol) of 2- (S) -methanesulfonylamino-3-methylbutanoic acid-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -amide and 2.5 g ( 7.5 mmol) of tributyltin azide the title compound as a light foam which has an Rr value of 0.45 [toluene / isopropanol / glacial acetic acid (170: 30: 2)].

• a) Eine Lösung von 2,17 g (10 mmol) BOC-L-Valin und 1,1 ml (10 mmol) N-Methylmorpholin in 20 ml Dichlormethan wird auf -5° gekühlt. Unter Rühren werden 1,23 ml (10 mmol) Pivalinsäurechlorid bei -5° zugetropft. Die Lösung wird 2 Stunden bei 0° gerührt und hierauf mit einer Lösung von 2,64 g (10 mmol) N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amin in 10 ml Dichlormethan tropfenweise versetzt. Es wird während 24 Stunden bei Raumtemperatur nachgerührt. Das Reaktionsgemisch wird mit 30 ml Dichlormethan verdünnt, nacheinander mit 1-n. Salzsäure (20 ml), gesättigter Kaliumbicarbonatlösung (10 ml) und Wasser gewaschen, getrocknet und i.V. eingedampft. Man erhält so das rohe N-Butyl-N-[2'-cyanobiphenyl-4-ylme- thyl]-2-[(S)-t-butyloxycarbonylamino] -3-methylbutansäureamid als niederschmelzende Masse.
• b) 4,7 g (10 mmol) rohes N-Butyl-N-[2'-cyanobiphenyl-4-ylmethyl]-2-[(S)-t-butyloxycarbonylamino]-3-methyl-butansäureamid wird in einem Gemisch von 30 ml Ameisensäure und 10 ml Dioxan gelöst und die Lösung 20 Stunden bei Raumtemperatur stehengelassen. Nach dem Eindampfen der Lösung i.V. wird der Rückstand zwischen Aethylacetat und 2 N Natronlauge verteilt, die organische Phase abgetrennt, mit Sole gewaschen, getrocknet und eingedampft. Man erhält so das 2-(S)-Amino-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-3-methyl-butansäureamid als gelbliches Oel, das ohne weitere Reinigung verwendet werden kann.
• c) In eine Lösung von 1,8 g (5 mmol) 2-(S)-Amino-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-3-methyl- butansäureamid und 1,4 ml (8 mmol) Hünigbase in 10 ml Dichlormethan wird unter Rühren eine Lösung von 0,75 g (6,5 mmol) Methansulfonsäurechlorid in 5 ml Dichlormethan getropft. Es wird noch weitere 5 Stunden bei Raumtemperaturgerührt, mit 50 ml Dichlormethan verdünnt und mit20 ml4-N Salzsäure extrahiert. Die Dichlormethan-Phase wird abgetrennt, nacheinander mit Wasser, 10 ml Bicarbonatlösung und Sole gewaschen, getrocknet und eingedampft. Man erhält so das rohe N-Butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-2-(S)-methansulfonylamino-3-methylbutansäureamid als gelbliches Oel vom R_rWert 0,56 [Toluol/Isopropanol/Eisessig (170:30:2)], das ohne weitere Reinigung in die nächste Stufe eingesetzt wird.

The starting material can be produced, for example, as follows:

• a) A solution of 2.17 g (10 mmol) BOC-L-valine and 1.1 ml (10 mmol) N-methylmorpholine in 20 ml dichloromethane is cooled to -5 °. 1.23 ml (10 mmol) of pivalic acid chloride are added dropwise at -5 ° while stirring. The solution is stirred at 0 ° for 2 hours and then a solution of 2.64 g (10 mmol) of N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) amine in 10 ml of dichloromethane is added dropwise. The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with 30 ml dichloromethane, successively with 1-n. Washed hydrochloric acid (20 ml), saturated potassium bicarbonate solution (10 ml) and water, dried and evaporated in vacuo. The crude N-butyl-N- [2'-cyanobiphenyl-4-ylmethyl] -2 - [(S) -t-butyloxycarbonylamino] -3-methylbutanoic acid amide is thus obtained as a low-melting mass.
• b) 4.7 g (10 mmol) of crude N-butyl-N- [2'-cyanobiphenyl-4-ylmethyl] -2 - [(S) -t-butyloxycarbonylamino] -3-methyl-butanoic acid amide is mixed in a mixture of 30 ml of formic acid and 10 ml of dioxane dissolved and the solution left for 20 hours at room temperature. After evaporating the solution in vacuo, the residue is partitioned between ethyl acetate and 2N sodium hydroxide solution, the organic phase is separated off, washed with brine, dried and evaporated. The 2- (S) -amino-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -3-methyl-butanoic acid amide is thus obtained as a yellowish oil which can be used without further purification.
• c) In a solution of 1.8 g (5 mmol) of 2- (S) -amino-N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -3-methyl-butanoic acid amide and 1.4 ml ( A solution of 0.75 g (6.5 mmol) of methanesulfonyl chloride in 5 ml of dichloromethane is added dropwise with stirring to 8 mmol of Hunig base in 10 ml of dichloromethane. The mixture is stirred for a further 5 hours at room temperature, diluted with 50 ml of dichloromethane and with 20 ml of 4N hydrochloric acid extra here. The dichloromethane phase is separated off, washed successively with water, 10 ml of bicarbonate solution and brine, dried and evaporated. The crude N-butyl-N- (2'-cyanobiphenyl-4-ylmethyl) -2- (S) -methanesulfonylamino-3-methylbutanoic acid amide is thus obtained as a yellowish oil with an R _r value of 0.56 [toluene / isopropanol / glacial acetic acid ( 170: 30: 2)], which is used in the next step without further purification.

Example 22:

Tablets, each containing 50 mg of active ingredient, for example 4-carboxy-4-methyipentanoic acid-N-propyi-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, can be prepared as follows :

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, the talc, the magnesium stearate and the highly disperse silicon dioxide are mixed in and the mixture is pressed into tablets each having a weight of 145.0 mg and an active substance content of 50.0 mg, which, if desired, provide partial notches for finer adjustment of the dosage could be.

Example 23:

Lacquer tablets, each containing 100 mg of active ingredient, for example 4-carboxy-4-methylpentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, can be prepared as follows :

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with a paste made from 15 g of corn starch and water (with heating) and granulated. The granules are dried, the rest of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is pressed into tablets (weight: 280 mg) and these are coated with a solution of hydroxypropylmethylcellulose and shellac in dichloromethane (final weight of the coated tablet: 283 mg).

Example 24:

In an analogous manner to that described in Examples 22 and 23, tablets and coated tablets containing another compound I or a pharmaceutically acceptable salt of a compound I, e.g. B. according to one of Examples 1 to 21, are prepared.

Claims (19)

1. A compound of the formula

wherein R _{1 is} an aliphatic hydrocarbon residue which is optionally substituted by halogen or hydroxy at a position higher than the β position to the nitrogen atom shown in the formula, a cycloaliphatic hydrocarbon residue or an araliphatic hydrocarbon residue; R ₂ 1 H-tetrazol-5-yl, carboxy, esterified carboxy, amidated carboxy, amino, substituted amino, acylamino, formyl, acetalized formyl, hydroxy, etherified hydroxy, S (O) _m- R, where m is 0, 1 or 2 is and R is hydrogen or an aliphatic hydrocarbon radical, alkanoyl, aminosulfonyl, N-substituted aminosulfonyl, P0 ₂ H ₂ , P0 ₃ H ₂ or S-substituted sulfonylamino, R _{3 is} carboxy, 1 H-tetrazol-5-yl, S0 ₃ H, P0 ₂ H ₂ , P0 ₃ H ₂ or haloalkanesulfonylamino; X represents straight-chain alkylene, which is optionally bridged by aliphatic means and / or is optionally substituted by an aliphatic hydrocarbon radical, or represents the structural element of the formula -X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another represent a bond or represent alkylene and Ph represents optionally substituted phenylene; the rings A and B independently of one another unsubstituted or by halogen, hydroxyl, etherified hydroxyl, S (O) _m -R, where m is 0, 1 or 2 and R is hydrogen or an aliphatic hydrocarbon radical, or an optionally interrupted by O and / or are optionally substituted by halogen or hydroxy-substituted aliphatic hydrocarbon radical; and either p and q are both 1 or p is 0 and q is 0 or 1; in free form or in salt form. 2. A compound according to claim 1 of formula I, wherein R _{1 is} lower alkyl, lower alkenyl, lower alkynyl, halogen in higher than the β-position to the nitrogen atom shown in formula I, halogen-lower alkyl, lower alkenyl or lower alkynyl, hydroxy in higher is hydroxy lower alkyl, lower alkenyl or lower alkynyl, cyclo lower alkyl, cyclo lower alkenyl, phenyl lower alkyl or phenyl lower alkenyl or lower alkynyl as the β position to the nitrogen atom shown in the formula; R ₂ 1H-tetrazol-5-yl, carboxy, carboxy, which is esterified by an alcohol, the alcoholic hydroxy function of which is bonded to lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy-lower alkyl, lower alkenyl or lower alkynyl, carbamoyl, the amino group of which is unsubstituted or by Lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl is mono- or independently disubstituted or is disubstituted by lower alkylene or lower alkyleneoxy lower alkylene, amino, by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl mono- or independently of one another disubstituted or disubstituted by lower alkylene or Niederalkylenoxyniederalkylen amino, mono-substituted by lower alkanoyl or benzoyl, amino, formyl, di-lower alkoxymethyl, 1,3-Dioxacyctoalk-2-yl, hydroxy, lower alkoxy, lower alkenyloxy, phenoxy, benzyloxy, S (O) _m R, wherein m is 0, 1 or 2 and R is what is lower, lower alkyl, lower alkenyl or lower alkynyl, lower alkanoyl, aminosulfonyl, aminosulfonyl in which the amino group is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or by lower alkylene or lower alkyleneoxy lower alkylene, disubstituted ₂ H ₂ , P0 ₃ H ₂ or sulfonylamino, in which the sulfur atom of the sulfonylamino group is monosubstituted by lower alkyl, lower alkenyl, lower alkynyl, halogen-lower alkyl, lower alkenyl or lower alkynyl, phenyl lower alkyl, lower alkenyl or lower alkynyl or phenyl, R ₃ carboxy, 1H-tetrazol-5-yl, S0 ₃ H, P0 ₂ H ₂ , P0 ₃ H ₂ or Is halogeno lower alkanesulfonylamino; X straight-chain lower alkylene, straight-chain lower alkylene in which one or, independently of one another, two methylene group (s) is (are) replaced by cyclone-lower alk-1,1-ylene, straight-chain lower alkylene which one or independently of one another is double, triple or quadruple by lower alkyl, Lower alkenyl or lower alkynyl is substituted, or straight-chain lower alkylene which is mono- or independently substituted two, three or four times by lower alkyl, lower alkenyl or lower alkynyl and in which one or independently two methylene group (s) of the corresponding unsubstituted straight-chain lower alkylene group existing methylene groups is (are) replaced by cycloniederalk-1,1-ylene; rings A and B are independently unsubstituted or by halogen, hydroxy, lower alkoxy, lower alkenyloxy, phenoxy, benzyloxy, S (O) _m -R, where m is 0, 1 or 2 and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl, lower alkyl , Lower alkenyl, lower alkynyl, halogeno lower alkyl, lower alkenyl or lower alkynyl, hydroxy lower alkyl, lower alkenyl or lower alkynyl, lower alkoxy lower alkyl optionally substituted by halogen or hydroxy, lower alkenyl or lower alkynyl or lower alkenyloxy lower alkyl optionally substituted by halogen or hydroxy , lower alkenyl or lower alkynyl are substituted; and either p and q are both 1 or p is 0 and q is 0 or 1; where phenyl in phenyl radicals per se and in phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, benzoyl, phenoxy and benzyloxy groups in each case unsubstituted or singly or independently of one another by (one) substituents selected from the group consisting of halogen, hydroxy , Lower alkoxy, lower alkyl and trifluoromethyl, means substituted phenyl; in free form or in salt form. 3. A compound according to claim 1 of the formula wherein R ₁ is lower alkyl, lower alkenyl or cyclo-lower alkyl; R ₂ 1 H-tetrazol-5-yl, carboxy, carboxy, which is esterified by an alcohol, the alcoholic hydroxy function of which is bonded to lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy-lower alkyl, lower alkenyl or lower alkynyl, carbamoyl, the amino group of which is unsubstituted or is mono- or independently disubstituted by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy lower alkylene, amino, by lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, lower alkenyl or lower alkynyl mono- or independently di-substituted or di-substituted by lower alkylene or Niederalkylenoxyniederalkylen amino, mono-substituted by lower alkanoyl or benzoyl, amino, formyl, di-lower alkoxymethyl, 1,3-Dioxacycloalk-2-yl, hydroxy, lower alkoxy, lower alkenyloxy, phenoxy, benzyloxy, S (O) _m -R , where m is 0, 1 or 2 and RW aterstoff, Niederalkyl, Niederalkenyl or Niederalkinyl, Niederalkanoyl, aminosulfonyl, aminosulfonyl, in which the amino group is mono- or independently disubstituted by Niederalkyl, Niederalkenyl, Niederalkinyl or Phenyl-lower alkyl,-Niederalkenyl oder -iederalkinyl or by Niederalkylen or Niederalkylenoxyniederalkylen, disubstituted ₂ H ₂ , P0 ₃ H ₂ or sulfonylamino, in which the sulfur atom of the sulfonylamino group is monosubstituted by lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, lower alkenyl or lower aikinyi, phenyl lower alkyl, lower alkenyl or lower alkynyl or phenyl; R _{3 is} halogeno lower alkanesulfonylamino, carboxy or 1H-tetrazol-5-yl; X straight-chain lower alkylene, straight-chain lower alkylene in which a methylene group has been replaced by cycloniederalk-1,1-ylene, straight-chain lower alkylene which is mono- or independently substituted two, three or four times by lower alkyl, lower alkenyl or lower alkynyl, or straight-chain lower alkylene which is mono- or independently substituted twice by lower alkyl, lower alkenyl or lower alkynyl and in which a methylene group of the methylene groups present in the corresponding unsubstituted straight-chain lower alkylene group is replaced by cyclone-lower alk-1,1-ylene represents rings A and B independently of one another unsubstituted or by halogen, hydroxy, lower alkoxy, S (O) _m- R, where m is 0, 1 or 2 and R is hydrogen or lower alkyl, lower alkyl, halogen-lower alkyl, hydroxy-lower alkyl, optionally substituted by halogen or hydroxy-lower alkoxy lower alkyl or optionally by halogen or hydrox y substituted lower alkenyloxy lower alkyl are substituted; and either p and q are both 1 or p is 0 and q is 0 or 1; wherein phenyl in phenyl radicals per se and in phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, benzoyl, phenoxy and benzyloxy groups in each case unsubstituted or mono- or independently of one another by (one) substituents selected from the group consisting of halogen, hydroxy, lower alkoxy , Lower alkyl and trifluoromethyl is substituted phenyl; in free form or in salt form. 4. A compound according to claim 1 of formula I, wherein R _{1 is} lower alkyl or lower alkenyl; R ₂ 1H-tetrazol-5-yl, carboxy, carboxy, which is esterified by an alcohol, the alcoholic hydroxy function of which is linked to lower alkyl or lower alkoxy-lower alkyl, carbamoyl, the amino group is unsubstituted or mono- or independently disubstituted by lower alkyl or phenyl-lower alkyl or is disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, amino, mono- or independently disubstituted by lower alkyl or phenyl-lower alkyl, or amino disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, by lower alkanoyl monos , Lower alkoxy, phenoxy, benzyloxy, S (O) _m -R, where m is 0, 1 or 2 and R is hydrogen or lower alkyl, lower alkanoyl, aminosulfonyl, P0 ₂ H ₂ , P0 ₃ H ₂ or sulfonylamino, in which the sulfur atom the sulfonylamino group is monosubstituted by lower alkyl, halogen lower alkyl, phenyl lower alkyl or phenyl; R _{3 is} carboxy or 1 H-tetrazol-5-yl; X represents straight-chain lower alkylene, straight-chain lower alkylene in which one methylene group has been replaced by cyclone-lower alk-1,1-ylene, or straight-chain lower alkylene which is mono- or independently substituted twice by lower alkyl; rings A and B are independently unsubstituted or substituted by halogen, hydroxy, lower alkoxy, S (O) _m- R, where m is 0, 1 or 2 and R is hydrogen or lower alkyl, or lower alkyl; p is 0, q represents 0 or 1; and ring B is bound in the 4-position of ring A; wherein phenyl in phenyl-lower alkyl, phenoxy and benzyloxy groups each represents phenyl which is unsubstituted or simply substituted by a substituent selected from the group consisting of halogen, lower alkoxy, lower alkyl and trifluoromethyl; in free form or in salt form. 5. A compound according to any one of claims 1-4 of the formula wherein X is the structural element of the formula -X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another for a bond or for C ₁ -C ₇ - Alklyen stand and Ph means phenylene; wherein phenylene is phenylene which is unsubstituted or substituted simply by a substituent selected from the group consisting of halogen, lower alkoxy, lower alkyl and trifluoromethyl; in free form or in salt form. 6. A compound according to any one of claims 1-5 of the formula wherein ring B is bonded in the 4-position of ring A; wherein phenyl in phenyl-lower alkyl, phenoxy and benzyloxy groups each represents phenyl which is unsubstituted or simply substituted by a substituent selected from the group consisting of halogen, lower alkoxy, lower alkyl and trifluoromethyl; in free form or in salt form. 7. A compound according to claim 1 of formula I, wherein R _{1 is} C ₁ -C ₄ alkyl or C ₃ -C ₅ alkenyl, R ₂ 1 H-tetrazol-5-yl, carboxy, C ₁ -C ₄ - Alkoxycarbonyl, carbamoyl, NC ₁ -C ₄ alkylcarbamoyl, N, N-di-C ₁ -C ₄ alkylcarbamoyl, C ₁ -C ₄ alkanoyl, aminosulfonyl or sulfonylamino, in which the sulfur atom of the sulfonylamino group is represented by C ₁ - C ₄ alkyl is monosubstituted; R _{3 is} carboxy or 1 H-tetrazol-5-yl; X straight-chain C ₁ -C ₇ alkylene in which a methylene group has been replaced by C ₃ -C ₇ cycloalk-1,1-ylene, or straight-chain C ₁ -C ₇ alkylene which is mono- or independently of one another by C ₁ -C ₄ alkyl is substituted; rings A and B are unsubstituted, p is 0, q is 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form. 8. A compound according to claim 1 of formula I, wherein R _{1 is} C ₁ -C ₄ alkyl or C ₃ -C ₅ alkenyl, R ₂ 1 H-tetrazol-5-yl, carboxy, C ₁ -C ₄ - Alkoxycarbonyl, carbamoyl, NC ₁ -C ₄ alkylcarbamoyl, N, N-di-C ₁ -C ₄ alkylcarbamoyl, C ₁ -C ₄ alkanoyl, aminosulfonyl or sulfonylamino, in which the sulfur atom of the sulfonylamino group is represented by C ₁ - C ₄ alkyl is monosubstituted; R _{3 is} carboxy or 1 H-tetrazol-5-yl; X stands for the structural element of the formula -X ₁ -Ph-X ₂ -, where X ₁ and X ₂ independently of one another stand for a bond or for C ₁ -C ₃ alkylene and Ph is phenylene; rings A and B are unsubstituted, p is 0, q is 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form. 9. A compound according to claim 1 of the formula I, in which R _{1 is} C ₁ -C ₄ -alkyl, R _{2 is} carboxy, C ₁ -C ₄ -alkoxycarbonyl or carbamoyl, R ₃ 1 is H-tetrazol-5-yl, X straight-chain C ₁ -C ₇ alkylene, in which a methylene group is replaced by C ₃ -C ₇ cycloalk-1,1-ylene, or straight-chain C ₁ -C ₇ alkylene which is mono- or independently of one another by C ₁ -C ₄ alkyl, the rings A and B are unsubstituted, p is 0, q is 1, the ring B is bonded in the 4-position of the ring A and R _{3 is} in the 2-position of the ring B. is bound, in free form or in salt form. 10. A compound according to claim 1 of the formula wherein R _{1 is} C ₁ -C ₄ alkyl, R _{2 is} carboxy, R ₃ 1 is H-tetrazol-5-yl, X is straight-chain C ₁ -C ₇ alkylene, in which a methylene group by C ₃ -C ₇ cycloalk- 1,1-ylene is replaced, or straight-chain C ₁ -C ₇ alkylene which is mono- or independently substituted twice by C ₁ -C ₄ alkyl, the rings A and B are unsubstituted, p is 0, q represents 1, ring B is bound in the 4-position of ring A and R ₃ is bound in a 2-position of Riges B, in free form or in salt form. 11. A compound according to claim 1 of formula I, wherein R _{1 is} C ₃ -C ₄ alkyl; R _{2 represents} carboxy; R _{3 is} H-tetrazol-5-yl; X is 2-methyl-but-1,3-ylene or 1,3-propylene in which the ω-methylene group is replaced by cyclohex-1, 1-ylene; rings A and B are unsubstituted; p is 0; q represents 1; ring B is bound in the 4-position of ring A; and R ₃ is attached in a 2-position of ring B; in free form or in salt form. 12. A connection selected from 3-carboxypropanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-carboxy-3-methylbutanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 4-carboxy-4-methyl-pentanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 4-carboxy-3,3-dimethyl-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 4-methoxycarbonyl-4-methylpentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 4-carboxy-4-methylpentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 4-carboxy-4-ethyl-hexanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 2-carboxybutanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 4-carboxy-4-ethylhexanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 4-carboxy-3,3-tetramethylene-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 4-Carboxy-3,3-tetramethylene-butanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-carboxy-3,3-tetramethylene-propanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-Carboxy-3,3-tetramethylene-propanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-Carboxy-3-ethylpentanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 4-carboxy-4,4-tetramethylene-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 4-Carboxy-4,4-tetramethylene-butanoic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 2-Carboxy-2-ethyl-butanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 2-Carboxy-2-ethyl-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 2-Carboxybutanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-carboxy-3-ethylpentanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide, in free form or in salt form; 3-Carboxy-3,3-pentamethylene-propanoic acid-N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-Carboxy-3,3-pentamethylene-propanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 5-carboxy-5,5-tetramethylene-pentanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 5-carboxy-5,5-tetramethylene-pentanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-carboxy-2,2-tetramethylene-propanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 3-Carboxy-2,2-tetramethylene-propanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; 2,2-pentamethylene-2-trifluoromethanesulfonylaminoethanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide, in free form or in salt form; and 2,2-Pentamethylene-2-trifluoromethanesulfonylaminoethanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl -4-ylmethyl] -amide, in free form or in salt form. 13. A connection selected from 4-carboxy-4,4-pentamethylene-butanoic acid-N-propyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide; 4-carboxy-4,4-pentamethylene-butanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide; N-propyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] isophthalic acid mono-amide; 2-carboxy-phenylacetic acid-N-butyl-N- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] amide; N-butyl-3-methyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -2- (S) -trifluoromethanesulfonylamino-butanoic acid amide; and 2- (S) -methanesulfonylamino-3-methyl-butanoic acid-N-butyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amide; each in free form or in salt form. 14. A compound according to any one of claims 1 to 13 in free form or in the form of a pharmaceutically acceptable salt, for use in a method for the therapeutic treatment of the human or animal body. 15. A compound according to any one of claims 1 to 14, in free form or in the form of a pharmaceutically acceptable salt, for use as an antihypertensive. 16. A pharmaceutical preparation containing as active ingredient a compound according to any one of claims 1 to 15 in free form or in the form of a pharmaceutically acceptable salt, optionally in addition to conventional pharmaceutical auxiliaries. 17. An antihypertensive pharmaceutical preparation according to claim 16. 18. A process for the preparation of a compound according to any one of claims 1 to 13 of the formula in free form or in salt form, characterized in that a) in a compound of the formula

wherein Z ₁ represents a convertible into R ₃ radical, or converted into a salt thereof, Z ₁ R ₃ or b) a compound of the formula

or a salt thereof with a compound of the formula

wherein either C (= 0) -Z _{2 represents} a carboxy group or a reactive derivative thereof and R ₂ ' is a radical R ₂ or in which R ₂ 'and C (= 0) -Z ₂ together form the group -C (= O) -OC (= O) -, or a salt thereof, and in each case, if desired, a process-appropriate or otherwise obtainable compound I, in free form or in salt form, converted into another compound I, separating a mixture of isomers obtainable according to the process and isolating the desired isomer and / or converting a free compound I obtainable according to the process into a salt or one obtainable according to the process Salt of a compound I is converted into the free compound I or into another salt. 19. Use of a compound according to any one of claims 1 to 15, in free form or in the form of a pharmaceutically acceptable salt, for the manufacture of a pharmaceutical preparation for the treatment of high blood pressure and / or heart failure.